Anticancer Drugs.

Anticancer Drugs

Cancer Uncontrolled multiplication and spread within the body of abnormal forms of body's own cells Cancer is a disease in which there is uncontrolled multiplication and spread within the body of abnormal forms of bodys own cells. It is one of the major causes of death in developed nations atleast 1 in 5 of the population of europe and north america can expect to die of cancer. Cancers are more common in aged people as life expectancy is increasing the incidence of cancers is also increasing, with the present methods of treatment one third of the patients are cured with local modalities of treatment (surgery or irradiation therapy) which are quite effective when the tumor has not metastatized. In metastasis systemic chemotherpy is required along with surgery or irradiation at present 50 % of the patients of cancer can be treated with chemotherapy contributing to cure in % of the patients. The terms cancer,malignant neoplasm and malignant tumor are synonymous

Cancer chemotherapy not as successful as antimicrobial chemotherapy
Metabolism in parasite differs qualitatively from host cells, while metabolism in cancer cells differ only quantitatively from normal host cells Hence target selectivity is more difficult in cancer cancer there is no substantial immune response Diagnostic complexity: delay in institution of treatment Hence target selectivity is more difficult in cancer*(exception in lymphoma , there is substantial selectivity)

Cancer cells differ from normal cells by
Uncontrolled proliferation De-differentiation & loss of function Invasiveness Metastasis

General toxicity of cytotoxic drugs
Nausea & Vomiting Bone marrow depression Alopecia Gonads: Oligospermia, impotence, ↓ ovulation Foetus: Abortion, foetal death, teratogenicity Carcinogenicity Hyperuricemia Immunosupression: Fludarabine Hazards to staff Majority of cytotoxic drugs have more profound effects on rapidly multiplying cells

Phases of cell cycle

Modalities of treatment in cancer
1/3 of patients can be cured, effective when tumor has not metastasized Surgery Radiotherapy Chemotherapy: 50 % of the patients can be treated with chemotherapy contributing to cure in % of patients Chemotherapy is essentially required with surgery or irradiation when metastasis has occurred

CLASSIFICATION - II: Depending on mechanism at cell level
Directly acting cytotoxic drugs: Alkylating agents Antimetabolites Natural products Antibiotics Vinca alkaloids Taxanes Epipodophyllotoxins Camptothecin analogs Enzymes Biological response modifiers Miscellaneous: Cisplatin, carboplatin Indirectly acting- by altering the hormonal mileau : Corticosteroids Estrogens & ERMs 5 alpha reductase inhibitors Gnrh agonists Progestins

Alkylating agents Nitrogen Mustards Ethyleneimine : Thiotepa
Meclorethamine, Melphalan, Chlorambucil, cyclophosphamide, ifosfamide Ethyleneimine : Thiotepa Alkyl Sulfonate: Busulfan Nitrosureas Carmustine,lomustine, streptozocin Triazines Dacarbazine, temozolamide

Antimetabolites Folate Antagonists Purine Antagonists
Methotrexate Purine Antagonists 6 Mercaptopurine, 6 Thioguanine, Azathioprine Pyrimidine antagonists 5 Fluorouracil, cytarabine, gemcitabine

Natural Products Antibiotics Vinca alkaloids Taxanes Enzymes
Actinomycin D, Doxorubicin, Daunorubicin, Bleomycin, Mitomycin C Vinca alkaloids Vincristine, Vinblastine, Vinorelbine Taxanes Paclitaxel, docetaxel Enzymes L-Asparginase Epipodophyllotoxins etoposide, tenoposide Camptothecin analogs Topotecan, irinotecan Biological response modifiers Interferons, Interleukins

Miscellaneous Agents Cisplatin Carboplatin Hydroxurea Procarbazine
Mitotane Imatinib

Hormones & antagonists
Corticosteroids Prednisolone Estrogens Ethinyl Estradiol SERM Tamoxifene, Toremifene SERD Fulvestrant Aromatase Inhibitors Letrozole, Anastrazole, Exemestane Progestins Hydroxyprogesterone Anti-androgens Flutamide, Bicalutamide 5- reductase Inhibitors finasteride, dutasteride GnRH analogs Naferelin, goserelin, leuoprolide

ALKYLATING AGENTS Chemically reactive compounds that combine most readily with nucleophilic centers. The term ‘alkylating agents’ is applied to compounds which, in a sense, alkylate the substance with which they react, by joining it through a covalent bond.

Types of Alkylating agents
Category Drugs Nitrogen mustards Cyclophosphamide, Mechlorethamine, Chlorambucil, Ifosamide, Melphalan Ethyleneimine Thiotepa Alkyl sulfonate Busulfan Nitrosoureas Carmustine, Lomustine Triazine Dacarbazine, temozolamide

MECHANISM OF ACTION Alkylating Agents
Form highly reactive carbonium ion Transfer alkyl groups to nucleophilic sites on DNA bases Results in All alkylating agents have alkyl groups and they can transfer this alkyl group to suitable receptor site. Alkylating agents in neutral or alkaline solution form highly reactive carbonium ion which is quaternary ammonium derivative(The carbon atom has only six electrons in its outer space so highly reactive). This carbonium ion is highly reactive and can react with groups like NH2, SH, OH or PO4 in physiologically important molecules in cell and render them unavailable for normal metabolic reactions. One more property of this carbonium ion is its nucleophilicity it can react with nucleic acid bases and inhibit DNA synthesis . The nitogen at guanine position 7 is especially more susceptible. So this results in cross linking inhibits DNA replication . Abnormal base pairing (alkylated guanine pairs with thymine instead of cytosine) results in production of defective protein DNA strands breakage – decreased cell proliferation Alkylation also damages RNA and proteins Non cycle specific Cross linkage Abnormal base pairing DNA strand breakage Alkylation also damages RNA and proteins ↓ cell proliferation

MECHANISM OF ACTION Contain chemical groups that can form covalent bonds with particular nucleophilic substances in the cell. Produce highly reactive carbonium ion intermediates. Forms covalent bond with electron donors like amine, hydroxyl and sulfhydryl groups. Alkylating agents are bifunctional, i.e. they have two alkylating groups. The nitrogen at position 7 (N7) of guanine, being strongly nucleophilic, is probably the main molecular target for alkylation in DNA.

N1 and N3 of adenine and N3 of cytosine may also be affected.
Being bifunctional they can cause intra- or interchain cross-linking, abnormal base pairing or chain scission which causes cell death,gene mutation or carcinogenesis. Destroy DNA structure directly, has strong toxicity to both proliferate or non-proliferate cells—Cell cycle non-specific agents Results in a block at G2 and subsequent apoptotic cell death.

NITROGEN MUSTARDS

NITROGEN MUSTARDS Mechlorethamine Melphalan Chlorambucil
Cyclophosphamide Ifosfamide

MECHANISM OF ACTION Nitrogen mustards inhibit cell reproduction by binding irreversibly with the nucleic acids (DNA). The specific type of chemical bonding involved is alkylation. After alkylation, DNA is unable to replicate and therefore can no longer synthesize proteins and other essential cell metabolites. Consequently, cell reproduction is inhibited and the cell eventually dies from the inability to maintain its metabolic functions.

MECHLORETHAMINE Transported into the cell by a choline uptake process.
MECHANISM OF ACTION:- Transported into the cell by a choline uptake process. Loses a chloride ion and forms a reactive intermediate That alkylates the N7 nitrogen of a guanine residue in one or both strands of a DNA molecule. Alkylation leads to cross-linkages that facilitates DNA strand breakage. Occur in both cycling and resting cells (therefore cell-cycle nonspecific) Proliferating cells are more sensitive to the drug, especially those in G1 and S phases.

Alkylation of guanine bases in DNA MOA OF MECHLORETHAMINE

PHARMACOKINETICS Very unstable, and solutions must be made up just prior to administration. Mechlorethamine is also a powerful vesicant (blistering agent) Administered only IV, because it can cause severe tissue damage if extravasations occurs.

RESISTANCE Decreased permeability of the drug
Increased conjugation with thiols such as glutathione Possibly increased DNA repair.

ADVERSE EFFECTS Severe nausea and a vomiting. Bone marrow depression
Immunosuppression. Extravasation - a serious problem.

THERAPEUTIC APPLICATIONS
Primarily in the treatment of Hodgkin's disease as part of the MOPP regimen (Mechlorethamine, Oncovin, Prednisone, Procarbazine) Also useful in the treatment of some solid tumors.

CYCLOPHOSPHAMIDE AND IFOSFAMIDE
Very closely related mustard agents that share most of the same toxicities. They are unique in that (1) They can be taken orally, and (2) They are cytotoxic only after generation of their alkylating species, following their hydroxylation by cytochrome P-450.

MECHANISM OF ACTION Most commonly used
Both cyclophosphamide and ifosfamide are first biotransformed to hydroxylated intermediates by the cytochrome P-450 system. The hydroxylated intermediates undergo breakdown to form the active compounds, phosphoramide mustard and acrolein. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step.

MECHANISM OF ACTION Pharmacological actions similar to mechlorethamine
Prodrug converted in body to active

MECHANISM OF ACTIVATION: CYCLOPHOSPHAMIDE
Inactive Cyclophosphamide Metabolised in the liver by P450 mixed function oxidases 4-hydroxycyclophos-phamide (Reversibly) forms aldophosphamide. Aldophosphamide is conveyed to other tissues Converted to phosphoramide mustard, the actual cytotoxic molecule

 MECHANISM OF ACTION Mesna Cyclophosphamide Aldophosphamide
Phosphoramide mustard Acrolein Hemorrhagic cystitis Hemorrhagic cystitis is specific toxicity of cyclophosphamide it is associated with dysuria, hematuria due to irritation of bladder mucosa by acrolein it is dose limiting toxicity. Mesna is also excreted in urine where it binds to and inactivates acrolein Should be given simultaneously and also 4-8 hrs after Acetyl cysteine can also be given Adequate hydration IV mesna (2 mercapto ethane sulfonate ) Cytotoxic effect Mesna

RESISTANCE Increased DNA repair Decreased drug permeability
Reaction of the drug with thiols(for example, glutathione). Cross-resistance, however, does not always occur.

PHARMACOKINETICS Preferentially administered by the oral route.
Minimal amounts of the parent drug are excreted into the feces (after biliary transport), or into the urine by glomerular filtration.

ADVERSE EFFECTS Alopecia, Nausea, Vomiting, Diarrhoea
Bone marrow depression, Leukocytosis Hemorrhagic cystitis Other toxicities on the germ cells resulting in amenorrhea, testicular atrophy, and sterility. High incidence of neurotoxicity in patients on high-dose ifosfamide.

USES OF CYCLOPHOSPHAMIDE
Neoplastic conditions Hodgkins and non hodgkins lymphoma Multiple myeloma Burkits lymphoma Neuroblastoma , retinoblastoma Breast Cancer, adenocarcinoma of ovaries Non neoplastic conditions Rheumatoid arthritis Nephrotic syndrome Wegeners granulomatosis

IFOSFAMIDE Congener of cyclophosphamide
Longer half life than cyclophosphamide Less alopecia and less emetogenic than cyclophosphamide Can cause hemorrhagic cystitis and severe neurological toxicity Used for germ cell testicular tumors and adult sarcomas Bronchogenic, breast, testicular, bladder, head and neck carcinomas, osteogenic sarcoma and some lymphomas. 1g vial+3 mesna ampoules 200mg for IV Bronchogenic, Breast, Testicular, Bladder , Head & Neck Carcinomas, Osteogenic Sarcoma& some lymphomas

CHLORAMBUCIL Slowest acting and least toxic alkylating agent
Main action on lymphoid tissue Drug of choice for long term maintenance therapy of CLL ( chronic lymphatic leukaemia), Hodgkin's disease and some solid tumours Also used in hodkins and other solid tumors

MELPHALAN Very effective in MULTIPLE MYELOMA & advanced ovarian cancer
Less irritant locally , less alopecia Adverse Effects : Bone marrow Depression Infections , diarrhea and pancreatitis Also used in advanced ovarian tumor, otherwise toxic effects and properties similar to mechlorethamine

THIO-TEPA Triethylene phosphoramide
Does not require to form active intermediate Active intravesicular agent can also be used topically in superficial bladder cancer Not well absorbed orally given IV High toxicity

BUSULFAN Highly specific for myeloid elements
Little effect on lymphoid tissue and G.I.T. ADVERSE EFFECT:- Hyperuricaemia; Pulmonary fibrosis & Sterility Drug of choice for chronic myeloid leukemia. Unique in that in conventional doses of busulfan exert few pharmacological actions other than myelosupression Other use- polycythemia vera Pigmentation of skin

NITROSOUREA Carmustine and lomustine are closely related nitrosoureas.

MECHANISM OF ACTION The nitrosoureas exert cytotoxic effects by an alkylation that crosslinks strands of DNA to inhibit its replication and eventually RNA and protein synthesis. Although they alkylate DNA in resting cells, cytotoxicity is expressed only on cell division; therefore nondividing cells can escape death if DNA repair occurs.

True nature of resistance is unknown
Probably results from DNA repair and reaction of the drugs with thiols.

PHARMACOKINETICS In spite of the similarities in their structures, carmustine - intravenously, lomustine - orally. Distribute to many tissues, Ability to readily penetrate into the CNS. The drugs undergo extensive metabolism. Lomustine is metabolized to active products. The kidney is the major excretory route.

ADVERSE EFFECTS Delayed hematopoietic depression An aplastic marrow
Renal toxicity Pulmonary fibrosis

Primarily employed in the treatment of brain tumors. They find limited use in the treatment of other cancers.

Triazenes Dacarbazine Temozolamide
Primary inhibitory action on RNA & protein synthesis Used in malignant melanoma, Hodgkin's disease Temozolamide New alkylating agent Approved for malignant glioma Rapidly absorbed after oral absorption & crosses BBB

1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects a. Nitrogen Mustards A. Mechlorethamine DNA cross-links, resulting in inhibition of DNA synthesis and function Hodgkin’s and non-Hodgkin’s lymphoma Must be given Orally Nausea and vomiting, decrease in PBL count, BM depression, bleeding, alopecia, skin pigmentation, pulmonary fibrosis B. Cyclophosphamide Same as above Breast, ovarian, CLL, soft tissue sarcoma, WT, neuroblastoma Orally and I.V. C. Chlorambucil Chronic lymphocytic leukemia Orally effective D. Melphalan Multiple myeloma, breast, ovarian E. Ifosfamide Germ cell cancer, cervical carcinoma, lung, Hodgkins and non-Hodgkins lymphoma, sarcomas Orally effective

1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects b. Alkyl Sulfonates A. Busulfan Atypical alkylating agent. Chronic granulocytic leukemia Orally effective Bone marrow depression, pulmonary fibrosis, and hyperuricemia c. Nitrosoureas 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects A. Carmustine DNA damage, it can cross blood-brain barrier Hodgkins and non-Hodgkins lymphoma, brain tumors, G.I. carcinoma Given I.V. must be given slowly. Bone marrow depression, CNS depression, renal toxicity B. Lomustine Lomustine alkylates and crosslinks DNA, thereby inhibiting DNA and RNA synthesis. Also carbamoylates DNA and proteins, resulting in inhibition of DNA and RNA synthesis and disruption of RNA processing. Lomustine is lipophilic and crosses the blood-brain barrier Hodgkins and non-Hodgkins lymphoma, malignant melanoma and epidermoid carcinoma of lung Orally effective Nausea and vomiting, Nephrotoxicity, nerve dysfunction C. Streptozotocin DNA damage pancreatic cancer Given I.V. Nausea and vomiting, nephrotoxicity, liver toxicity

d. Ethylenimines 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects A. Triethylene thiophosphoramide (Thio-TEPA) DNA damage, Cytochrome P450 Bladder cancer Given I.V. Nausea and vomiting, fatigue B. Hexamethylmelamine (HMM) DNA damage Advanced ovarian tumor Given orally after food Nausea and vomiting, low blood counts, diarrhea d. Triazenes 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects A. Dacarbazine (DTIC) Blocks, DNA, RNA and protein synthesis Malignant Melanoma, Hodgkins and non-Hodgkins lymphoma Given I.V. Bone marrow depression, hepatotoxicity, neurotoxicity, bleeding, bruising, blood clots, sore mouths.

ANTIMETABOLITES These are analogues related to normal components of DNA or of coenzymes involved in nucleic acid synthesis. They competitively inhibit utilization of the normal substrate or get themselves incorporated forming dysfunctional macromolecules. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects are S phase (and-therefore cell-cycle)specific.

Antimetabolites Folate Antagonists Purine Antagonists
Methotrexate Purine Antagonists 6 Mercaptopurine, 6 Thioguanine, Azathioprine Pyrimidine antagonists 5 Fluorouracil, cytarabine, gemcitabine Chemical substance which takes part in cellular metabolic reactions is called metabolite Antimetabolite is a chemical substance which by virtue of its close structural resemblence to metabolite blocks its action it can achieve this by 2 methods By preventing the combination of metabolite with its specific enzyme By itself combining with specific enzyme and getting converted to either metabolically inactive or harmful to cell ( lethal synthesis)

METHOTREXATE Structurally related to folic acid
Acts as an antagonist of that vitamin by inhibiting dihydrofolate reductase ,the enzyme that convert folic acid to its active form coenzyme form tetrahydrofolic acid (THF4). It therefore acts as an antagonist of that vitamin. Folate plays a central role in a variety of metabolic reactions involving the transfer of one-carbon units.

MECHANISM OF ACTION (a) Inhibition Of Dihydrofolate Reductase:
After absorption of folic acid from dietary sources or from that produced by intestinal flora, the vitamin undergoes reduction to the tetrahydrofolate form (FH4) by the intracellular NADPH-dependent dihydrofolate reductase. Methotrexate enters the cell by an active transport process, which normally mediates the entry of N5-methyl FH4. At high MTX concentrations, the drug can diffuse into the cells.

MTX has an unusually strong affinity for dihydrofolate reductase, and effectively inhibits the enzyme. Its inhibition can only be reversed by a thousand-fold excess of the natural substrate, dihydrofolate or by administration of leucovorin, which bypasses the blocked enzyme and replenishes the folate pool. (b) Consequences Of Decreased FH4: Inhibition of dihydrofolate reductase deprives the cell of the various folate coenzymes and leads to decreased biosynthesis of thymidylic acid, methionine and serine, and the purines (adenine and guanine). Thus eventually to depressed DNA, RNA and protein synthesis and to cell death.

c. Polyglutamated MTX: Like tetrahydrofolate itself, MTX becomes polyglutamated within the cell, a process that favors intracellular retention of the compound due to its larger size and increased negative charge.

Methotrexate Adenine, guanine, thymidine , methionine, serine
One of most commonly used anticancer agents Cell cycle specific drug acts in S phase Methotrexate has antineoplastic, immunosuoressant and anti-inflammatory action It produced the first striking although temporary remission of leukemia and first cure for choriocarcinoma Mechanism of action of methotrexate: methotrexate structurally resembles folic acid , it competitively inhibits dihydrofolate reductase enzyme and blocks conversion of DHFA to THFA THFA is an essential coenzyme required for one carbon transfer reactions in denovo purine synthesis and synthesis of thymidilate , amino acid conversions which are required for DNA SYNTHESIS it also inhibits RNA and protein synthesis. More toxic to rapidly dividing cells likw bone marrow Adenine, guanine, thymidine , methionine, serine

RESISTANCE Nonproliferating cells are resistant to methotrexate.
Due to amplification (production of additional copies) of the gene that codes for dihydrofolate reductase resulting in increased levels of this enzyme. Enzyme affinity also be diminished. Reduced influx of MTX, caused by a change in the carrier- mediated transport responsible for pumping MTX into the cell.

Methotrexate, often in combination with other drugs, is effective against acute lymphocytic leukemia, choriocarcinoma, Burkitt's lymphoma in children, breast cancer, and head and neck carcinomas. High-dose MTX is curative for osteogerric sarcoma and choriocarcinoma; treatment is followed by administration of leucovorin to rescue the bone marrow. In addition, low-dose MTX is effective as a single agent against certain inflammatory diseases, such as severe psoriasis and rheumatoid arthritis.

Pharmacokinetics a. Administration and distribution:
Methotrexate is readily absorbed at low doses from the GI tract, but it can also be administered by intramuscular (IM), intravenous (IV), and intrathecal routes. High concentrations of the drug are found in the intestinal epithelium, liver and kidney, as well as in ascites and pleural effusions. MTX is also distributed to the skin.

Methotrexate is also metabolized to poly-glutamate derivatives.
b. Fate: Although folates found in the blood have a single terminal glutamate, most intracellular folates are converted to polyglutamates. Methotrexate is also metabolized to poly-glutamate derivatives. High doses of methotrexate undergo hydroxylatlon at the 7 position. This derivative is less water soluble, and may lead to crystalluria. Therefore, it is important to keep the-urine alkaline and the patient well hydrated to avoid renal toxicity. Excretion of the parent drug and the 7-OH metabolite occurs via the urine.

5. Adverse effects: Commonly observed toxicities:
Most frequent toxicities are stomatitis, myelosuppression, erythema, rash, urticaria, alopecia, nausea, vomiting, and diarrhea. b. Renal damage: Although uncommon during conventional therapy, renal damage is a complication of high-dose methotrexate. c. Hepatic function: Hepatic function should be monitored. Long term use may lead to fibrosis.

d. Pulmonary toxicity: Children being maintained on methotrexate may develop cough, dyspnea, fever, and cyanosis. e. Neurologic toxicities: These are associated with intrathecal administralion, and include subacute meningeal irritation, stiff neck, headache, and fever. Seizures, encephalopathy, or paraplegia occur rarely. Long-lasting effects, such as learning disabilities. f. Contraindications: Because methotrexate is teratogerlic and an abortifacient it should be avoided in pregnancy.

Purine antagonists 6 Mercaptopurine 6 Thioguanine Azathioprine

6-MERCAPTOPURINE The drug ,6 mercaptopurine (6-MP) is the thiol analog of hypoxanthine. It and thioguanine (6-TG) were the first purine analogs to prove benificial for treating neoplastic disease. Azathioprine, an immunosuppressant, exerts its effects after conversion to 6- MP.

SITE OF ACTION: a. Formation of nucleotide: To exert its antileukemic effect, 6- mercaptopurine must penetrate target cells and be converted to the corresponding nlucleotide, 6- mercaptopurine ribose phosphate. The addition of the ribose phosphate is catalyzed by the salvage pathway enzyme, hypoxanthine- guanine phosphoribosryl -transferase (HGPRT).

b. Inhibition of purine synthesis:
Inhibit the first step of de novo purine ring biosynthesis as well as formation of AMP and xanthinylic acid (XMP) from inosinic acid (IMP). c. Incorporation into nucleic acids: Dysfunctional RNA and DNA result from incorporation of guanylate analogs generated from the unnatural nucleotides. Thio-IMP is dehydrogenated to thio- GMP, which after phosphorylation to di- and triphosphates, can be incorprated into RNA. The deoxyribonucleotide analogs that are also formed are incorporated into DNA.

6 Mercaptopurine (HGPRT):
Ribonucleotide 1. Nucleotide formation: To exert its antileukemic effect, 6-MP must penetrate target cells and be converted to the nucleotide analog, 6-thioinosinic acid TIMP. The addition of the ribose phosphate is catalyzed by enzyme, hypoxanthine-guanine phosphoribosyl transferase (HGPRT). 2. Inhibition of purine synthesis: A number of metabolic processes involving purine biosynthesis and interconversions are affected by, TIMP. Like adenosine monophosphate (AMP), guanosine monophosphate (GMP), and inosine monophosphate (IMP), TIMP can inhibit the first step of de novo purine-ring biosynthesis (catalyzed by glutamine phosphoribosyl pyrophosphate amidotransferase) by feed back mechanism. TIMP also blocks the formation of AMP and xanthinuric acid from inosinic acid. 3. Incorporation into nucleic acids: TIMP is converted to thioguanine monophosphate (TGMP), which after phosphorylation to di- and triphosphates can be incorporated into RNA. The deoxyribonucleotide analogs that are also formed are incorporated into DNA. This results in nonfunctional RNA and DNA. (HGPRT): hypoxanthine-guanine phosphoribosyl transferase

Purine antagonist: 6-mercaptopurine
Converted in the cells to ribonucleotide of 6-mercaptopurine Suppresses denovo biosynthesis of purines No DNA synthesis

2. Resistance Resistance is associated with
an inability to biotransform 6-MP to the corresponding nucleotide because of dcreased level of HGPRT an increased dephosphorylation; or increased metabolism of the drug to thiouric acid.

3. Therapeutic applications
6-MP is used principally in the mainteinance of remission in acute lymphoblastic leukemia (ALL). 4. Adverse effects: Side effects include nausea, vomiting, and diarrhea. Bone marrow depression is the chief toxicity. Hepatotoxicity has also been reported.

5. PHARMACOKINETICS a. administration and metabolism:
Absorption by the oral route is erratic. The drug is widely distributed throughout the body except for the cerebrospinal fluid. 6-MP undergoes metabolism in the liver to the 6-methyl mercaptopurine (S- CH3) derivative or to thiouric acid. The latter reaction is catalyzed by xanthine oxidase. Because allopurinol, a xanthine oxidase inhibitor, is frequently administered to cancer patients receiving chemotherapy to reduce hyperuricemia, it is important to decrease the dose of 6-MP in these individuals to avoid accumulation of the drug and exacerbation of toxicities. b. Excretion: The parent drug and its metabolites are excreated by the kidney.

6 Mercaptopurine Allopurinol 6 MP 6 Thiouric acid Inactive metabolite
Xanthine oxidase TPMT Well absorbed orally, metabolized rapidly by xanthine oxidase, use of xanthine oxidase inhibitor allopurinol decreases the inactivation of 6 MP, xanthine oxidase also required in uric acid synthesis, so allopurinol may be used in cancer chemotherapy to reduce dose of 6 MP and also decrease the hyperuricaemia 6 MP ALSO METABOLISED BY METHYLATION IN PRESENCE OF ENZYME THIOPURINE METHYL TRANSFERASE, GENTIC DEFICIENCY OF THIS ENZYME MAKES INDIVIDUAL MORE SUSCEPTIBLE TO 6 MP toxicity , while over expression is important method of resistance. Azathiprine is also substrate for xanthine oxidase but 6 thiguanine is not. 6 Thiouric acid Inactive metabolite

Fludarabine Phosphorylates intracellularly to form triphosphate
Inhibits DNA polymerase and gets incorporated to form dysfunctional DNA Effective in slow growing tumors: (apoptosis) Use: Chronic lymphoblastic leukemia (CLL) and non hodgkins Adverse events: chills, fever, opportunistic infection, myelosupression Promotes tumor apoptosis

Pyrimidine antagonists
5 fluoruracil Cytosine arabinoside (Cytarabine) Gemcitabine

5-FLUOROURACIL (5-FU) A pyrimidine analog, Fluorouracil is an analogue of thymine in which the methyl group is replaced by a fluorine atom. A stable fluorine atom at position 5 of the uracil ring. The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic acid. Depriving the cell of one of the essential precursors for DNA synthesis.

1. Site of action: It has two active metabolites: 5-FdUMP and 5- FdUTP. 5-FdUMP inhibits thymidylate synthetases and prevents the synthesis of thymidine, a major building block of DNA. 5-FdUTP is incorporated into RNA by RNA polymerase and interferes with RNA function.

Thymidilate synthetase
5 fluorouracil FdUMP = fluorodeoxyuridine monophosphate 5 FU FdUMP Thymidilate synthetase Thymidine Monophosphate dUMP 5 fluoro uracil is converted in body to corresponding nucleotide fluorodeoxyuridine monophosphate, Fluorinated analog of pyrimidine acts by inhibiting thymidilate synthesis Also gets incorporated into DNA in place of uracil Uses: topically intreatment of premalignant keratosis Even resting cells are more affected though rapidly multipling cells are more susceptible Toxic to bone marrow , alimentary epitheliumand CNS Administered by slow IV infusion to prevent first pass metabolism. Uses : stomach , colon, breast ovaries , liver, skin cancers DNA Synthesis (Selective failure)

Pyrimidine Antagonist: 5-Fluorouracil (Analogue of uracil)
Converted to 5-fluoro-2-deoxy uridine monophosphate Inhibits thymidilate synthesis Blocks conversion of deoxyuridilic acid to deoxythymidilic acid Inhibition of DNA synthesis

2.Resistance: Lost the ability to convert 5-FU into active form Altered or increased thymidylate synthetase Increased rate of 5- FU catabolism. 3. Theraputic applications:- primarily in the treatment of slowly growing, solid-tumors=(for example: colorectal, breast, ovarian, pancreatic, and gastric carcinomas) Treatment of superficial basal cell carcinomas.

4. Pharmacokinetics: Severe toxicity to the GI tract Given intravenously or topically. Penetrates well into all tissues including the CNS. Metabolized in the liver 5. Toxicities: Nausea, vomiting, diarrhea, and alopecia, severe ulceration of the oral and GI mucosa, bone marrow depression and anorexia

Cytarabine Cytosine arabinoside, ara-C
An analog of 2'-deoxycytidine in which the natural ribose residue is replaced by D-arabinose. Acts as a pyrimidine antagonist. Site of action: ara-C sequentially phosphorylated to the corresponding nucleotide, cytosine arabinoside triphosphate (ara-CTP), in order to be cytotoxic. It is S-phase (hence cell-cycle) specific. Ara-C is also incorporated into DNA and can terminate chain elongation.

2. Resistance: Defect in the transport process A change in phosphorylating enzymes An increased pool of the natural dCTP nucleotide. 3. Therapeutic indications: The major clinical use is in acute nonlymphocytic leukemia in combination with 6-TG and daunorubicin.

4. Pharmacokinetics: Given IV Distributes throughout the body, but does not penetrate the CNS. Injected intrathecally Undergoes extensive oxidative deamination Excreted by the kidney.

5. Adverse effects: Nausea, Vomiting, Diarrhea Severe myelosuppression Hepatic dysfunction Seizures or altered mental states.

GEMCITABINE S-phase specific A deoxycytidine antimetabolite
Undergoes intracellular conversion to gemcitabine monophosphate via the enzyme deoxycytidine kinase it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine triphosphate Gemcitabine is similar to cytarabine in its structure and metabolic pathway Gemcitabine crosses the cell membrane better than cytarabine It has a longer intracellular retention and a greater affinity for deoxycytidine kinase in comparison to cytarabine

GEMCITABINE Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA strands Due to an addition of a base pair before DNA polymerase is stopped, Gemcitabine inhibits both DNA replication and repair Gemcitabine-induced cell death has characteristics of apoptosis

GEMCITABINE Therapeutic Uses
variety of solid tumors very effective in the treatment of pancreatic cancer Small cell lung cancer carcinoma of the bladder, breast, kidney, ovary, and head and neck

C. Antimetabolites 1. Mechanism of Action 2. Clinical application
3. Route 4. Side effects 1. Methotrexate inhibits formation of FH4 (tetrahydrofolate) from folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR); since FH4 transfers methyl groups essential to DNA synthesis and hence DNA synthesis blocked. Choriocarcinoma, acute lymphoblastic leukemia (children), osteogenic sarcoma, Burkitt's and other non-Hodgkin‘s lymphomas, cancer of breast, ovary, bladder, head & neck Orally effective as well as given I.V. bone marrow depression, intestinal lesions and interference with embryogenesis. Drug interaction: aspirin and sulfonamides displace methotrexate from plasma proteins. 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects 2. Pyrimidine Analogs: Cytosine Arabinoside inhibits DNA synthesis most effective agent for induction of remission in acute myelocytic leukemia; also used for induction of remission acute lymphoblastic leukemia, non-Hodgkin's lymphomas; usually used in combination chemotherapy Orally effective bone marrow depression

1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects 3. Purine analogs: 6-Mercaptopurine (6-MP) and Thioguanine Blocks DNA synthesis by blocking conversion of AMP to ADP; also blocks first step in purine synthesis. Feedback inhibition blocks DNA synthesis by inhibiting conversion of GMP to GDP; also blocks first step in purine synthesis by feedback inhibition most effective agent for induction of remission in acute myelocytic leukemia; also used for induction of remission acute lymphoblastic leukemia, non-Hodgkin's lymphomas; usually used in combination chemotherapy Orally effective bone marrow depression,

Plant Alkaloids Vinca Alkaloids Podophyllotoxins Camptothecins Taxanes
All derived from plant extracts

VINCA ALKALOIDS Vinblastine Vincristine Vinorelbine

Vinca alkaloids Obtained from periwinkle plant ( Vinca Rosea)
Vincristine, vinblastine, vinorelbine

MECHANISM OF ACTION Binds to the microtubular protein tubulin in a dimeric form The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly Depolymerization of the microtubules occurs Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation CCS agents- M phase Derived from the vinca rosea, the periwinkle plant Microtubules are an important part of the cytoskeleton and the mitotic spindle “Spindle Poison”

Vinblastine and Vincristine
Bind to β-tubulin (drug tubulin complex) inhibits its polymerization into microtubules No intact mitotic spindle cell division arrested in metaphase

Mechanism of action VX and VBL are both cell-cycle specific and phase specific, because they block mitosis in metaphase (M phase). Their binding to the microtubular protein, tubulin, is GTP dependent and blocks the ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates consisting of tubulin dimers and the alkaloid drug are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation Resistance: Resistant cells have been shown to have an enhanced efflux of VX, VBL, and VRB via P-glycoprotein in the cell membrane. Alterations in tubulin structure may also affect binding of the vinca alkaloids.

Resistance Enhanced efflux of vincristine and vinblastine and several other drugs. Alterations in tubulin structure

Therapeutic applications
Vincristine - Acute leukemias, lymphomas, Wilm’s Tumor and Neuroblastoma Vinblastine – Lymphomas, Neuroblastomas,Testicular cancer and Kaposi’s sarcoma Vinorelbine – non-small cell lung carcinoma and breast Cancer

PHARMACOKINETICS Given Intravenously
Concentrated and metabolized in the liver Excreted into bile and feces. Doses must be modified in patients with , impaired hepatic function or biliary obstruction.

ADVERSE EFFECTS a. Shared toxicities: Vincristine and vinblastine
Phlebitis or cellulitis, nausea, vomiting, diarrhea, and alopecia. b. Unique toxicities: Vinblastine is a more potent myelosuppressant. Vincristine associated with peripheral neuropathy, Gastrointestinal problems.

Comparison between Vincristine Vinblastine Alopecia more common
Peripheral & autonomic neuropathy & muscle weakness (CNS) Constipation Uses: (Childhood cancers) ALL , Hodgkins, lymphosarcoma, Wilms tumor, Ewings sarcoma Less common Less common, temp. mental depresssion Nausea, vomiting, diarrhoea uses Hodgkins disease & other lymphomas , breast cancer, testicular cancer AFE: Unpredictable oral absorption, extensively conc in platelets, vinca alkaloids are not well absorbed by oral route Highly irritant drugs so given continously by iv infusion, vinca alkaloids are conc and metabolized by CYP450 in liuver excreted in bile in liver dysfunction decrease the dose Phenytoin, phenobarbitone, carbamezepine may induce the metabolism and griseofulvin inhibits metabolism Vinorelbine: semisynthetic derivative for ca breast, testicular cancer, epithelial ovarian cancers.

TAXANES Paclitaxel & docetaxel
Plant product obtained from bark of Pacific Yew ( Taxus Brevifolia) & European Yew (Taxus Buccata)

PACLITAXEL Better known as taxol,
Paclitaxel is the first member of ,the taxane family used in cancer chemotherapy. A semi-synthetic paclitaxel is now available.

SITE OF ACTION Paclitaxel binds reversibly to tubulin
But it promotes polymerization and stabilization of the polymer rather than disassembly. The overly stable microtubules formed in the presence of paclitaxel are dysfunctional, thereby causing the death of the cell.

Mechanism of action Cell cycle arrested in G2 and M phase
Taxanes bind to beta tubulin subunits of microtubules at a site different from binding site of vinca alkaloids, colchicine, podophyllotoxin, unlike vinca alkaloids they promote polymerization of microtubules & inhibit depolymerization, leading to stabilization of polymerized microtubules and arrests cells in mitosis and eventually leads to activation of apoptosis The stabilization of microtubules is damaging to cells because of disturbances in in the dynamics of various microtubule dependent structures that are required for functions like mitosis, maintainence of cellular morphology, locomotion and secretion. Cell cycle arrested in G2 and M phase

Resistance Efflux of the drug The mutation in tubulin structure.

Therapeutic indications
Advanced ovarian cancer and Metastatic breast cancer. Small-cell lung cancer, Squamous-cell carcinoma of the head and neck, Several other cancers. Combination therapy with other anticancer drugs

PHARMACOKINETICS Infused over 3-4 hours.
Hepatic metabolism and biliary excretion are responsible for elimination of paclitaxel.

ADVERSE EFFECTS Hypersensitivity Neutropenia Peripheral neuropathy
Transient asymptomatic bradycardia Alopecia vomiting Diarrhea

Epipodophyllotoxins Etoposide & tenoposide
Semisynthetic derivatives of podophyllotoxins podophyllum peltatum (plant glycoside)

MECHANISM OF ACTION Etoposide and Teniposide
forms complex with DNA and topoisomerase ІІ prevent resealing of broken DNA strand Cell death Act in S & G2 phase

Etoposide& Teniposide
Teniposide is an analogue with similar properties PK- orally well absorbed and distributes to most body tissues. Elimination is mainly via kidneys Clinical use – Testicular and lung ca. in combination with cytotoxic agents. Non-hodgkin’s lymphoma and AIDS related Kaposi’s Sarcoma Toxicity – Etoposide and Teniposide are GI irritants and cause alopecia and bone marrow suppression Type I topoisomerase cuts one strand of a DNA double helix, relaxation occurs, and then the cut strand is reannealed. Type II topoisomerase cuts both strands of one DNA double helix, passes another unbroken DNA helix through it, and then reanneals the cut strand. Testicular tumors in combination with bleomycin or cisplatin Tenoposide used in ALL

CAMPTOTHECINS Topotecan Irinotecan

Camptothecin analogs TOPOTECAN and IRINOTECAN:-
Derived from camptotheca accuminata Inhibit Topoisomerase I: No resealing of DNA after strand has untwisted Topoisomerase I modulates supercoiling of DNA by complexing with it and nicking one of its strands

TOPOTECAN and IRINOTECAN
PK- Irinotecan – prodrug – converted to active metabolite in liver Topotecan is eliminated renally Irinotecan and its metabolite eliminated in bile and faeces Topotecan: Used in metastatic ovarian cancer Major toxicity is bone marrow depression Irinotecan Used in metastatic cancer of colon/rectum Toxicity: diarrhoea, neutropenia, thrombocytopenia, cholinergic side effects Damage DNA by inhibiting an enzyme that cuts and relegates single DNA strands during normal DNA repair processes

ANTIBIOTICS 1. ANTHRACYCLINES(DOXORUBICIN & DAUNORUBICIN)
2. DACTINOMYCIN(ACTINOMYCIN D) 3. PLICAMYCIN(METHRAMYCIN) 4. MITOMYCIN (MITOMYCIN C) 5. BLEOMYCIN 6. MITOZANTRONE

Dactinomycin Mechanism of Action
Intercalates into the minor grooves of double helix between G-C base pairs of DNA ad interferes with the movement of RNA polymerase along the gene preventing transcription. May also cause strand breaks and stabilise DNA topoisomerase II complex. 3 D’s intercalate between base pairs Ribosomal RNA formation being most sensitive to drug action DNA replication is less effected, while protein is blocked The degree of cytotoxic effect is determined by the cells ability to accumulate and retain the antibiotic Drug is mainly excreted in the bile

Dactinomycin Uses: Adverse effects Wilms tumor,
gestational choriocarcinoma Adverse effects bone marrow supression Irritant like meclorethamine sensitizes to radiation, and inflammation at sites of prior radiation therapy may occur Gastrointestinal adverse effects Mechanism of action: The drug intercalates into the minor groove of the double helix between guanine-cytosine base pairs of DNA,8 forming a stable dactinomycin-DNA complex. The complex interferes primarily with DNA-dependent RNA polymerase, although at high doses, dactinomycin also hinders DNA synthesis. The drug also causes single-strand breaks, possibly due to action on topoisomerase II or by generation of free radicals. Adverse effects: The major dose-limiting toxicity is bone marrow depression. The drug is immunosuppressive. Other adverse reactions include nausea, vomiting, diarrhea, stomatitis, and alopecia. Extravasation during injection produces serious problems. Dactinomycin sensitizes to radiation, and inflammation at sites of prior radiation therapy may occur.

Anthracyclines Doxorubicin Daunorubicin

Mechanism of Action High-affinity binding to DNA through intercalation, resulting in blockade of DNA and RNA synthesis DNA strand scission via effects on Top II Binding to membranes altering fluidity Generation of the semiquinone free radical and oxygen radicals The generation of free radicals lead to cardiac toxicity thru oxygen radical mediated damage to membranes

Doxorubicin & Daunorubucin

Toxicity Bone marrow depression Total alopecia Cardiac toxicity
Cardiac toxicity involves excessive intracellular production of free radicals with the myocardium, Tx with antioxidants like vitamin E

Therapeutic Uses Doxorubicin- carcinomas of the breast, endometrium, ovary, testicle, thyroid, and lung, Ewing’s sarcoma, and osteosarcoma Daunorubicin- acute leukemia

Bleomycins Group of metal-chelating glycopeptide antibiotics obtained from Streptomyces verticullus. Produces chelation of copper or iron ions which produces superoxide ions that interacts with DNA. Degrade preformed DNA, causing chain fragmentation and release of free bases.

Bleomycin Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis The DNA fragmentation is due to oxidation of a DNA- bleomycin-Fe(II) complex and leads to chromosomal aberrations Cell cycle specific Active in G2 phase

Bleomycin Uses : Adverse effects:
Epidermoid cancers of skin, oral cavity, genitourinary tract, esophagus Testicular tumors Hodgkins lymphoma Adverse effects: Pneumonitis Fatal pulmonary fibrosis Hyper pigmentation spares bone marrow

Mitomycin CCNS , given intravenously and is rapidly cleared by hepatic metabolism Mechanism of Action Bioreductive alkylating agent that undergoes metabolic reductive activation through an enzyme-mediated reduction to generate an alkylating agent that cross-links DNA Toxicity Severe myelosuppression Renal toxicity Interstitial pneumonitis Therapeutic Uses Squamous cell carcinoma of the cervix Adenocarcinomas of the stomach, pancreas, and lung 2nd line in metastatic colon cancer Is thought to be a CCNS alkylating agent Hypoxic tumor stems cell of solid tumors Useful in hypoxic tumors

Plicamycin Mechanism of Action
Binds to DNA through an antibiotic-Mg2+ complex This interaction interrupts DNA-directed RNA synthesis Toxicity Bleeding disorders Liver toxicity Therapeutic Uses Testicular cancer Hypercalcemia

Mitoxantrone Analogue of doxorubicin with lower cardiotoxicity
It has a narrow range of utility: in acute nonhaemolytic leukaemia, chronic myelogenous leukaemia, non-hodgkin lymphoma and carcinoma breast. Major toxicity is marrow depression and mucosal inflammation.

MISCELLANEOUS Cisplatin Carboplatin Hydroxyurea Procarbazine
L-Asparaginase Imatinib

CISPLATIN Pt NH3 Cl A member of the platinum coordination complex class Because of cisplatin's severe toxicity, carboplatin was developed. The therapeutic effectiveness of the two drugs is similar but their pharmacokinetics, patterns of distribution and dose-limiting toxicities differ.

MECHANISM OF ACTION Similar to that of the alkylating agents.
Cisplatin enters the cell and binds to the N7 of guanine of DNA, forming inter- and intra-strand crosslinks. The resulting cytotoxic lesion inhibits both DNA and RNA synthesis. Both drugs can also bind to proteins and other compounds containing SH groups. Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to the actions of these drugs in GI and S.

Mechanism of action of cisplatin
Cisplatin enters cells Cl- Forms highly reactive platinum complexes Intra strand & interstrand cross links DNA damage Inhibits cell proliferation

2.Resistance Elevated glutathione levels Increased DNA repair
3. Therapeutic applications Treatment of solid tumors such as metastatic testicular carci noma in combination with vinblastine and bleomycin Ovarian carcinoma in combination with cyclophosphamide Alone for bladder carcinoma

4. Pharmacokinetics Cisplatin and carboplatin are administered IV
Given intraperitoneally for ovarian cancer. Over 90% is bound to serum proteins. Highest concentrations are found in liver, kidney, intestinal, testicular and ovarian cells, but little penetrates into the CSF. The renal route is for excretion.

5. Adverse effects Severe vomiting Nephrotoxicity Hypomagnesemia
Hypocalcemia Ototoxicity and tinnitus Mild bone marrow suppression Neurotoxicity Hypersensitivity reactions. Myelosuppression.

CARBOPLATIN Better tolerated
Nephrotoxicity , ototoxicity , neurotoxicity low Less emetogenic But thrombocytopenia and leukopenia may occur Less plasma protein binding Use: primarily in ovarian cancer of epithelial origin Squamous cell carcinoma of head and neck Excreted by kidneys t1/2 4to 6 hrs Oxaliplatin : less myelosupression but more paresthesia

L-Asparaginase Catalyzes the deamination of asparagine to aspartic acid and ammonia. Enzyme used chemotherapeutically Derived from bacteria.

1. Mechanism of action Some neoplastic cells require an external source of asparagine Because of their limited capacity to make sufficient L-asparagine to support growth and function. L-Asparaginase hydrolyzes blood asparagine and thus deprives the tumor cells of this nutrient required for protein synthesis.

L-asparaginase

2. Resistance: Increased capacity of tumor cells to synthesize asparagine 3. Therapeutic application: Childhood acute lymphocytic leukemia in combination with vincristine and prednisone. 4. Pharrnacokinetics: Administered either IV or IM Because it is destroyed by gastric enzymes. 5. Adverse effects: Hypersensitivity reactions Decrease in clotting factors Liver abnormalities, Pancreatitis, Seizures and coma

Procarbazine MOA: forms hydrogen peroxide, which generates free radicals that cause DNA damage Inhibits DNA and RNA synthesis. Used in the treatment of Hodgkin's disease as part of the "MOPP regimen and also other cancers. Procarbazine rapidly equilibrates between the plasma and the CSF after oral or parenteral administration. Drug are excreted through the kidney.

Toxicity Bone marrow depression Nausea vomiting Diarrhea
Neurotoxic, causing symptoms drowsiness to hallucinations to paresthesias. A disulfiram-type reaction Procarbazine is both mutagenic and teratogenic.

HYDROXYUREA MOA:- It blocks the conversion of ribonucleotides to deoxyribonucleotides by inhibiting the enzyme ribonucleoside diphosphate reductase-thus interferes with DNA synthesis. Exerts S-phase specific action. Therapeutic value:- chronic myeloid leukaemia, psoriasis and in some solid tumours. Myelosuppression is the major toxicity.

Ribonucleoside diphosphate reductase
Hydroxyurea Ribonucleoside diphosphate reductase Ribonucleotides Deoxyribonucleotides Hydroxyurea Uses: CML, Polycythemia, psoriasis Dose: 20-30 mg/kg /day orally Adverse effects Myelosuppression (Minimal) Hypersensitivity Hyperglycemia Hypoalbuminemia Blocks enzyme Less GI toxicity

IMATINIB Selective anti-cancer drug whose development was guided by knowledge of specific oncogene MOA: specific anticancer drug acts on specific oncogene. Inhibits tyrosine kinase activity of protein product of B cr-Abl oncogene that is expressed in chronic myelogenous leukemia→ as result proliferation of oncogene inhibited→ apoptosis results.

IMATINIB RESISTANCE:- Due to mutation in Bcr-Abl tyrosine kinase PK:-
well absorbed orally , metabolized in liver , metabolites excreted in faeces through bile. T1/2 – 18 hrs A/Es- Abdominal pain, vomitting, fluid retention,myalgia and CHF USE: (1) CML (2) GI stromal tumors ( C-kit tyrosine kinase)

Hormonal therapy Hormonal therapy is one of the major modalities of medical treatment for cancer It involves the manipulation of the endocrine system through exogenous administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones

Used for several types of cancers derived from hormonally responsive tissues, including the breast, prostate, endometrium, and adrenal cortex. Most familiar example of hormonal therapy in oncology is the use of the selective estrogen-response modulator tamoxifen for the treatment of breast cancer, although another class of hormonal agents, aromatase inhibitors, now have an expanding role in that disease.

Hormones & antagonists
Corticosteroids Prednisolone Estrogens Ethinyl Estradiol SERM Tamoxifene, Toremifene SERD Fulvestrant Aromatase Inhibitors Letrozole, Anastrazole, Exemestane Progestins Hydroxyprogesterone Anti-androgens Flutamide, Bicalutamide 5- reductase Inhibitors finasteride, dutasteride GnRH analogs Naferelin, goserelin, leuoprolide

Glucocorticoids Marked lympholytic effect so used in acute leukaemias & lymphomas, They also Have Anti-inflammatory effect Increase appetite, prevent anemia Produce sense of well being Increase body weight Supress hypersensitivity reaction Control hypercalcemia & bleeding Non specific antipyretic effect Increase antiemetic effect of ondansetron Prevent anemia: prevent acceletated erythrocytic destruction, They effectively counter hemolytic and hemorrhagic complications accompanying chronic lymphocytic and malignant lymphomas, Prednisolone is generally started in doses of 60 – 100 mg daily in divided doses and then depending on response reduced to maintenance dose of mg /day The use of this compound in the treatment of lymphomas arose when it was observed that patients with Cushing's syndrome, which is associated with hypersecretion of cortisol, have lymphocytopenia and decreased lymphoid mass. [Note: At high doses, cortisol is also lymphocytolytic and leads to hyperuricemia due to the breakdown of lymphocytes.] Prednisone is primarily employed to induce remission in patients with acute lymphocytic leukemia and in the treatment of both Hodgkin's and non-Hodgkin's lymphomas. Glucocorticoids have some secondary role in hormone responsive breast cancers, they are also valuable for treatment of complications like treatment of hypercalcemia, hemolytic anemias, thrombocytopenia, incresed intracranial tension, mediastinal edema occuring after radiotherapy, they afford symptomatic relief by mood elevating and antipyretic effects and also adjuvants of antiemetics. Useful in treating cerebral edemas due to intracranial cerebral metastasis

Estrogens Physiological antagonists of androgens
Thus used to antagonize the effects of androgens in androgen dependent prostatic cancer Fofesterol Prodrug , phosphate derivative of stilbesterol mg IV initially later mg orally Fosfesterol is activated to slibesterol in prostatic tissue and acheives high conc in prostatic tissue thus it is used in prostrate cancer Adverse effects – impotence and gynaecomastia

Anti-Estrogens Tamoxifen (SERMs) Raloxifene (SERMs) Faslodex

Tamoxifen Selective estrogen receptor modulator (SERM), have both estrogenic and antiestrogenic effects on various tissues Binds to estrogen receptors (ER) and induces conformational changes in the receptor Has antiestrogenic effects on breast tissue. The ability to produce both estrogenic and antiestrogenic affects is most likely due to the interaction with other coactivators or corepressors in the tissue and the binding with different estrogen receptors, ER and ER Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes is blocked or altered Resulting in decreased estrogen response. Most of tamoxifen’s affects occur in the G1 phase of the cell cycle

Selective Estrogen Receptor Modulators (SERMs)
Tamoxifen : Non steroidal antiestrogen Agonistic: Uterus, bone, liver, pitutary Antagonistic: Breast and blood vessels SERMS are non steroidal synthetic agents whose agonist or antagonist action on estrogen receptors are tissue selective, produces beneficial estrogenic actions in some tissues (bone, brain, liver), and prevent certain deleterious effect in breast and endometrium by exhibiting antagonistic or no action on ER Tamoxifen: Non steroidal antiestrogen related structuraly to slilbesterol, given orally it competes with the circulating estrogen for cytoplasmic estrogen receptor binding site, the metabolites of tamoxifen have much stronger affinity for receptors and are not easily displaced by circulating estradiol. At low concentration they have cytostatic effect on ER positive cells, higher conc cause cytotoxic effect . Because of antagonistic action in breast DOC in treatment of ca breast in ER+ AS WELL as some ER- breast cancer also male breast

Tamoxifen Toxicity Hot flashes Fluid retention nausea

Tamoxifen Therapeutic Uses
Tamoxifen can be used as primary therapy for metastatic breast cancer in both men and postmenopausal women Patients with estrogen-receptor (ER) positive tumors are more likely to respond to tamoxifen therapy, while the use of tamoxifen in women with ER negative tumors is still investigational When used prophylatically, tamoxifen has been shown to decrease the incidence of breast cancer in women who are at high risk for developing the disease

Selective Estrogen Receptor Down regulator (fulvestrant)
Pure estrogen antagonist USES: Metastatic ER+ Breast Ca in postmenopausal women MOA: Inhibits ER dimerization & prevents interaction of ER with DNA ER is down regulated resulting in more complete supression of ER responsive gene function USES: Metastatic ER+ Breast Ca in postmenopausal women which has stopped responding to tamoxifen Higher affinity for ER probably accounts for efficacy in tamoxifen resistant cases

Anti-Androgen Flutamide Antagonizes androgenic effects
approved for the treatment of prostate cancer

Anti-androgen FLUTAMIDE
MOA: bind to androgen receptor inhibit androgen effects. USE: prostatic carcinoma. ADR: hot flushes Hepatic dysfunction Gynecomastia.

Anti androgens BICALUTAMIDE : Androgen Receptor antagonists
Palliative effect in metastatic Prostatic Ca

Aromatase Inhibitors Aminogluthethimide Anastrozole

Aminogluthethimide Mechanism of Action
Inhibitor of adrenal steroid synthesis at the first step, conversion of cholesterol of pregnenolone Inhibits the extra-adrenal synthesis of estrone and estradiol Inhibits the enzyme aromatase that converts androstenedione to estrone

Aminogluthethimide Toxicity
Dizziness Lethargy Visual blurring Rash Therapeutic Uses ER- and PR-positive metastatic breast cancer

AROMATASE INHIBITOR: ANASTRAZOLE:
Inhibit aromatase w/c catalyses conversion of androstenedione (androgenic precursor) to estrone ( estrogenic hormone) USE: advanced breast cancer ADR: hot flushes, bone and back pain,Dyspnea DOSE: 1mg orally daily

Aromatase Inhibitors Letrozole Orally active non steroidal compound
MOA : Inhibits aromatisation of testosterone & androstenedione to form estrogen. Uses : Breast Ca Aromatization of A ring of testesterone and androstenedione is final and key step in production of estrogens estradiol and estrone in body, in addition to circulating hormone the locally produced hormone may play an important role in breast cancer development, exemestane also aromatase inhibitor

Gonadotropoin-Releasing Hormone Agonists
Leuprolide Goserelin

Gonadotropoin-Releasing Hormone Agonist Mechanism of Action
Agents act as GnRH agonist, with paradoxic effects on the pituitary Initially stimulating the release of FSH and LH, followed by inhibition of the release of these hormones Resulting in reduced testicular androgen synthesis These analogs are more potent than the natural hormone and fxn as GnRH agonist, with paradoxic effects on the pituitary

GnRH agonists NAFERELIN : nasal spray / SC inj
↓FSH & LH release from pituitary- ↓ the release of estrogen & testosterone USE : Breast Ca, Prostatic Ca PROGESTINS: Hydroxyprogesterone – used in metastatic endometrial Ca. A/E: bleeding

Gonadotropoin-Releasing Hormone Agonist Toxicity
Gynecomastia Edema thromboembolism

Gonadotropoin-Releasing Hormone Agonist Therapeutic Uses
Metastatic carcinoma of the prostate Hormone receptor-positive breast cancer

5- reductase inhibitors
Finasteride Prostate volume Symptom score Peak urine flow rate DHT level in prostate Orally active DHT levels ↓ Benign prostatic hyperplasia Dose: 5mg/day Also used for prevention of hair loss Side effects: Loss of libido & impotence in 5 % pts.

Hormones and related agents -
GLUCORTICOIDS – Prednisolone - most commonly used glucorticoid in Ca.chemo. Used for combination chemotherapy in leukemia and lymphomas ESTROGEN – Physiological antagonists of androgens Antagonizes the effects of androgens in androgen dependent prostatic tumors- fosfestrol ( prodrug) – stilboestrol (prostatic tissue) TAMOXIFEN- Anti-oestrogen mainly used in the palliative treatment in hormone dependent breast ca Glucocorticoids – combined with ondansetron for management for mnx of chemotherapy induced vomitting Fosfestrol achieves high conc. In prostate - prefered

PROGESTINS – Medroxyprogesterone acetate, hydroxyprogesterone caproate and megestrol 2nd line hormonal therapy for metastatic hormone dependent breast ca and endometrial ca ANTI-ANDROGENS – Flutamide and bicalutamide – bind to androgen receptor – inhibit androgen actions Prostatic ca, used along with GNRH agonist – strategy known as ‘complete androgen blockade’ Flutamide can cause – hot flushes, hepatic dysfunction and gynaecomastia

Goserelin, Nafarelin and leuprolide act as agonist of GnRH
GnRH agonists - Goserelin, Nafarelin and leuprolide act as agonist of GnRH used in advanced prostatic ca GnRH antagonist – Cetrorelix, ganirelix and abarelix are antagonist of GnRH Decrease the release of gonadotropins without causing initial stimulation Can be used in prostatic ca without the risk of flare up reaction Gnrh agonist- continuous adm of these agents leads to transient release of LH and FSH (and thus flaring up of symptoms in prostatic ca) followed by inhibition of release of gonadotropins. .

AROMATASE Inhibitors – Anastrozole, letrozole etc
Aromatase is the enzyme responsible for conversion of androstenedione ( androgen precursor) to estrone (estrogenic hormone) 1st gen.- aminoglutethimide 2nd gen.- formestane, fadrozole,rogletimide 3rd gen.- exemestane,letrozole,anastrozole Aromatase inhibitors – useful in advanced breast ca. Adverse effects – hot flushes, arthralgia and fatigue Aminogluthethimide causes adrenal insufficiency and myelosuppression

THANK YOU -PHARMA STREET

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