1. ANTI CANCER DRUGS

2. INTRODUCTION
Definition: Cancer is a disease characterized by uncontrolled multiplication and spread of abnormal forms of the body's own cells.
The terms cancer, malignant neoplasm (neoplasm simply means 'new growth') and malignant tumor are synonymous.
TWO TYPES OF TUMOUR
1 BENIGN TUMOUR
2 MALIGNANT TUMOUR 7

3. THE PATHOGENESIS OF CANCER.
Cancer cells manifest four characteristics that distinguish them from normal cells
uncontrolled proliferation
dedifferentiation and loss of function
invasiveness
Metastasis

4. General principles for cancer therapy
The cells of a solid tumour can be divided into 3 compartments:
Compartment A
Continuously dividing cells
Compartment B
Resting cells in G0 phase
Have an ability to enter the cell cycle
Compartment C
No ability to divide

5. Only the cells in the compartment A i. e
Only the cells in the compartment A i.e. the dividing cells are susceptible to the main currently available cytotoxic drugs. But these cells are only 5% of the entire tumour.
The cells in the compartment B tend to pose a problem as they are not susceptible to cancer chemotherapy but are likely to enter the compartment A following the course of chemotherapy.
Most of the currently available anti cancer drugs are antiproliferative. They have no specific inhibitory effect on invasiveness, the loss of differentiation or the tendency to metastatise. Their main action is on S phase of the cell cycle and hence results into the DNA damage causing apoptosis.

6. Lastly , the cancer chemotherapy also acts on the normal tissues and thereby they produce a some general toxic effects like :
bone marrow suppression (myelosuppression) resulting in decreased leucocyte production and hence increased resistance to infection.
Impaired wound healing
Loss of hair
Damage to the gastrointestinal epithelium
Growth retardation in children
Sterility
Teratogenecity
They can themselves be carcinogenic
Kidney damage due to excess urate deposition in the tubules ( due to extensive purine catabolism)
Severe nausea and vomitting ( reduced patient compliance)

7. Drugs used in cancer chemotherapy
Cytotoxic Drugs
Alkylating agents
Antimetabolites
Antimitotics
Cytotoxic antibiotics
Plant derivatives
Hormones
Miscellaneous agents

8. Alkylating agents
The nitrogen at position 7 (N7) of guanine is strongly nucleophilic and is the main target for the alkylating agents. N1 and N3 of adenine and N3 of cytosine may also be affected.
Most of these agents are bifunctional i.e. they have two alkylating groups and can cause inter as well as intrachain cross-linking.
This can not only interfere with transcription but also replication .

9. Other effects of alkylation at guanine N7 are excision of the guanine base with main chain scission, or pairing of the alkylated guanine with thiamine instead of cytosine and eventually substitution of the GC pair by an AT pair.
The effects of this alkylation are manifested during S phase, resulting in block at G2 phase and subsequent apoptotic cell death.
Side effects:
bone marrow depression,
git disturbances at very high doses.
neurotoxicity
With prolonged use it can lead to sterility

10. Intrastrand and interstrand crosslinking in DNA

11. Types of alkylating agents are:
1. Nitrogen Mustards
Cyclophosphamide
Ifosphamide
Chlorambucil
Melphalan
Mecholrethamine
Bendamustine
Glufosfamide
3. Agents with trizene group
Dacarbazine
Procarbazine
Timozolamide
4. Ethelenamines
Thiotepa
Hexamethylmelamine
5. Agents with sulfate group
Busulfan
Platinum compounds:
Cisplatin, carboplatin
2. Nitrosoureas
Lomustine
Carmustine
Semustine
Streptozocine

12. Cyclophosphamide/ifosfamide are prodrugs Metabolized to aldophosphamide Tissues Acrolein Phosphoramide mustard causes hemorrhagic cystitis Alkyl group which causes N7 guanine and causes inhibition of DNA
Hepatic cytochrome oxidase
Treatment: Intake of fluids and –SH group donors like Mesna

13. Other imp points of alkylating agents:
Streptozocine:
destroys the beta cells of pancreas so approved for treatment of insulinoma. Also used to induce diabetes mellitus in experimental animals.
Busulfan:
Selective action on bone marrow, depressing the formation of granulocytes and platelets in low dose and red blood cells in high dose.
Use: chronic granulocytic leukemia, as a preparative for bone marrow transplantation
Main side effect is pulmonary fibrosis and neurotoxicity (seizures)
Also can cause adrenal suppression
Estramustine: Estrogen + mechlorethamine
Approved for the treatment of prostatic carcinoma
S/E – Gynaecomastia, loss of libido, thromboembolism

14. Cisplatin:
M/A:
it has a platinum atom surrounded by two chloride atoms and two ammonia groups. When it enters the cell the cl- group dissociates leaving the reactive complex to interact with DNA. It causes intrastrand crosslinking between N7 and O6 of adjacent guanine molecules leading to denaturation of DNA.
Side effects:
nephrotoxicity,(hydration and diuresis required)
Severe nausea and vomiting (ondansetron given)
Tinnitus and hearing loss
Low myelotoxicity
Others: peripheral neuropathies, huperuricaemia, anaphylactic reactions.
Use: solid tumours of testes and ovary
Carboplatin: derivative of cisplatin
More myelotoxicity
Less neurotoxocity, nephrotoxicity , ototoxicity, nausea and vomiting.
Cisplatin – max S/E and min potency
Carboplatin – intermediate
Oxaliplatin – min S/E and max potency

15. Antimetabolites
These drugs act in the s-phase of the cell cycle so only dividing cells are responsive
Folic acid analogues Purine analogues Pyrimidine analogues
Methotrexate mercaptopurine 5-flourouracil
Pemetrexed thioguanine Capecitabine
cladrabine Gemcitabine
Pentostatin Cytarabine
Fludrabine
Methotrexate:
Inhibitor of dihydrofolate reductase enzyme which is required for synthesis of thymidylate and hence DNA formation.
At high dose – by diffusion enters the normal cells and inhibits DNA formation in the normal cells

16. S/E: BM suppression, diarrhoea, mucositis due to inhibition of rapidly proliferating cells
Drug of choice for overdose:
Folinic acid or leucovorin or citovorum factor. It directly gets converted to tetrahydrofolate bypassing the requirement of dihydrofolate reductase.
On the surface of cancer cells, there is an influx pump which takes in methotrexate at low dose. Inside the cells it binds with polyglutamine
Forms methotrexate polyglutamine complex which serves as reservoir of methotrexate leading to long lasting effect.
MTX has affinity for cells having high chromosome no. like placental, fetal and germ cells so it is drug of choice for choriocarcinoma in which single drug treatment is used.

17. Eliminated by kidney- tubular secretion by acidic pumps.
NSAIDS can saturate these pumps leading to decreased secretion of MTX causing toxicity.
Uses:
Almost all types of cancers, Burkitt’s lymphoma, choriocarcinoma, breast carcinoma, osteosarcoma.
It also has immunosuppressive property so it is used for organ transplant, RA, IBD, Psoriasis, Ectopic pregnancy.
Resistance: - mutation of influx pumps
- induction of efflux pumps
- mutation of DHFRase enzyme
Pemetrexed:
inhibitor of thymidine synthase.
Folic acid or vit B12 can reduce the toxicity of pemetrexed
Approved for tumour of mesothelioma
S/E- peripheral neuropathy in hand and foot region called as hand-foot syndrome.

18. Mechanism of action methotrexate and fluorouracil

19. Pyrimidine analogues:
5-FU is the prodrug
Active metabolite is 5- fluorodeoxyuridine monophosphate
Cells are unable to differentiate between 5F-dUMP and dUMP
5F-dUMP
CH thymidine synthase
Fluorothymidine
Inhibits DNA synthesis because of incorporation of modified neucleotide
Leucovorin given with 5FU increases formation of fluorothymidine causing increased effect of 5FU. This concept is used in colorectal cancer.
FOLFOX regimen of colorectal cancer. FOL- Folinic acid
FOLFIRI F- 5FU, OX- oxaliplatin, IRI- irinotecan

20. Metabolized at the level of lung tissue by endothelial enzymes.
Given by i.v route
Alternative: capecitabine which is prodrug of 5FU given by oral route.
Gemcitabine/Cytarabine:
Act as prodrugs. Combines with 3PO4 groups and converts to
Gemcitabine triphosphate modified nucleotides which with
Cytarabine triphosphate the help of DNA polymerase gets incorporated into DNA inhibiting DNA synthesis
Gemcitabine use: non beta cells cancer of pancreas
S/E: flu like symptoms

21. 6-methylmercaptopurine HGPRTase Purine structure DNA polymerase
Purine analogue:
6-MP ( prodrug)
6-methylmercaptopurine
HGPRTase
Purine structure
DNA polymerase
Incorporation in DNA. So inhibition of DNA synthesis.
Metabolized by xanthine oxidase to form uric acid.
Some part is metabolized by methyl transferase enzyme.
6-Tiagabine: acts in the same way as 6-MP but metabolized only by methyl transferase enzyme.
Azathioprine: prodrug of 6-MP. Used only as immunosuppressive.

22. Pentostatin: inhibitor of adenosine deaminase. Used in hairy
Pentostatin: inhibitor of adenosine deaminase. Used in hairy cell leukemia.
Cladribine: used in hairy cell leukemia
Antimitotics
Vinka alkaloids
Texans
Ixebepilone
Vinka alkaloids:
vincristine, vinblastine, vinorelbine
MOA: inhibition of spindle formation
S/E: - SIADH
- Bone marrow suppression
- Peripheral neuropathy.

23. Taxanes: Paclitaxel, docitexal, cabazitexal
MOA: inhibition of spindle formation
Approved for the treatment of breast carcinoma
Paclitaxel + carboplatin: treatment of choice in ovarian cancer.
S/E: Hypersensitivity reaction and to inhibit it paclitexal is combined with albumin to form abpaclitaxel
bone marrow suppression
peripheral neuropathy
Ixebepilone: MOA same as texans but more potent than paclitexal so used in treatment of paclitexal resistant breast cancer
Advantage – no hypersensitivity reaction

24. Anti tumour antibiotics
Anthracycline antibiotics
Mitoxantrone
Mitomycin c
Bleomycin
Actinomycin D
Most imp mechanism of action – Free radicle formation
S/E:
Cardiotoxicity – cardiomyopathy after 2-3 months.
Treatment– dexrazoxane, alpha – tocoferol – they are free radicle scavengers
Bone marrow suppression

25. ANTHRACYCLINES:
Doxorubicin,Idarubicin, epirubicin, aclarubicin, mitoxantrone.
Mechanism of action of Doxorubicin: inhibits both DNA and RNA synthesis by an effect on topoisomerase II (DNA gyrase)
Given by i.v. infusion
Epirubicin is less cardiotoxic than doxorubicin.
Mitoxantrone has dose-related cardiotoxicity .
Dactinomycin:
Mechanism : it intercalates in the minor groove of DNA and interferes with the movement of RNA polymerase and thus prevents transcription.

26. Red urine
Radiation recall phenomenon – seen after many years of radiation. Epithelial damage and vesicles seen at the same site after taking drugs
Most common S/E – Nausea, vomitting, diarrhoea
MITOXANTRONE
Same as above but cardiotoxicity is rarely seen.
Associated with blue urine, blue nails, blue sclera
Indication – Multiple sclerosis

27. MITOMYCIN C
Functions as a bifunctional alkylating agent
Very potent drug but causes toxicity when used systemically.
So not used via systemic route.
Uses
Tracheal stenosis and
Oesophageal stenosis
Superficial bladder cancer
BLEOMYCIN
With the help of Fe2+ bleomycin converts O2 to free radicles and causes DNA damage. It is the only anticancer drug that can be given via any route.

28. Metabolized by bleomycin hydrolase which is present all over the body except skin and lung. So the main S/E is lung and skin fibrosis.
It causes little myelosuppression.
RADIOACTIVE IODINE : I131: Used in treatment of thyroid tumours.

29. TOPOISOMERASE INHIBITORS
Etoposide Irinotecan Teniposide Topotecan
(Topoisomerase II) (TopoisomeraseI)
campothecins
All drugs eliminated by kidney. Caution in CRF
Except Irinotecan which is a drug metabolized by liver to active SN38 which is eliminated by kidney.
Cholinergic properties – diarrhoea present since day 1 of therapy.
USE – colorectal carcinoma.

30. Hormones:
Glucocorticoids: They have inhibitory effect on lymphocyte proliferation
Used in leukemias and lymphomas
Estrogens: Fosfeterol (a prodrug which is activated by acid phosphatase in prostatic tissue ) block the effect of androgens in androgen-dependent prostatic tumours.
Estrogen can also be used to recruit resting mammary cells from compartment B to compartment A thus allowing greater killing efficiency of cytotoxic drugs.
Progesterons: Megesterol and medroxyprogesterone have been useful in endometrial neoplasms and renal tumours.

31. Gonadotrophin- releasing hormone analogues:
Goserelin can inhibit gonadotrophin release.
Used to treat advanced breast cancer in postmenopausal women and prostate cancer.
Analogue of somatostatin:octreotide is used to treat various hormone secreting tumours of the git such as VIPomas, glucagonomas, gastrinomas. These tumors express somatostatin receptors, activation of which inhibits cell proliferation and hormone secretion.

32. Hormone antagonists:
Anti-estrogens: Tamoxifen is effective in hormone dependent breast cancer. In breast tissue, Tamoxifen competes with endogenous oestrogens for oestrogen receptors and inhibits transcription of oestrogen- responsive genes.
Also has cardioprotective effect by preventing oxidation of LDL.
Anti-androgens: Flutamide and cyproterone are used in prostate tumours.
Adrenal hormone synthesis inhibitor: Formestane acts at a late stage of sex hormone synthesis by inhibiting enzyme aromatase. Trilostane and aminoglutethimide also inhibit sex hormone synthesis.

33. Miscellaneous agents:
L-ASPERGINASE(Crisantaspase)
Only enzyme used as anticancer drug.
Metabolize aspergine to urea or ammonia
Normal cells can form all aspergine on their own but cancer cells cannot form their own aspergine and depend on plasma aspergine. L-asperginase depletes plasma aspergine causing cancer cell death.
USE- Leukemias
S/E
Hyperammonemia
Protein deficiency
Clotting and anticlotting factors are proteins so clotting disturbances
Hupoalbuminemia

34. HYDROXYUREA
Inhibitor of ribonucleotide reductase enzyme which converts ribose sugar to deoxyribose sugar incorporated in DNA
Acts on the S phase of the cell cycle
Side-effect: myelosupression

35. Miscellaneous agents:
Imatinib mesylate: it is a small molecule which inhibits signalling pathway kinases. It inhibits platelet- derived growth factor.
It also inhibits cytoplasmic kinase which is a unique factor in pathogenesis of chronic myeloid leukemia and hence licensed for the treatment of this tumour.
Biological response modifiers: agents which enhance the host response.
Examples: interferon γ, aldesleukin and tretinoin.

36. Monoclonal antibodies
Rituximab:
Attaches to CD20 proteins on B cells and kills B cells by complement mediated lysis or by inducing apoptosis.
Use: B cell lymphoma
Side effects: hypotension, chills and fever initially
Hypersensitivity reaction
May make cardiovascular diseases worse
Trastuzumab:
Binds to a protein called Her2/neu. (member of the epidermal growth factor receptor family- receptors with integral tyrosine kinase activity)
Use: in some patients with breast cancer, these receptors are overexpressed
Side effects : similar to rituximab

37. GEMTUZUMAB-OZAGAMYCIN COMBINATION
MOA – DNA inhibition by formation of free radicles.
CELL CYCLE SPECIFIC agents
NON CELL CYCLE SPECIFIC agents
G1/S –Etoposide
Topoisomerase inhibitors
S – Antimetabolite
Hydroxyurea
Alkylating agents
G2/M – Etoposide
Bleomycin
All anticancer antibiotics except bleomycin
M – vinka alkaloids
taxens
Ixebepilone
Estramustine
Platinum compounds

38. REGIMENS FOR DIFFERENT TUMOURS:
DRUGS
COAP
Cyclophosphamide+Vincristine+ cytarabine+prednisolone
POMP
Prednisolone+Oncovin(Vincristine)+ Mtx+Purinethol(6-MP)
CART
Cytarabine+Asparginase+Rubidomycin(daunorubicin)+ 6-TG
MOPP
Mechlorethamine+Oncovin+ Procarbazine+Prednisolone
VAMP
Vincristine+Amethopterine(MTX) MP+Prednisolone

39. MALIGNANCY
FIRST LINE THERAPY
SECOND LINE DRUGS
Acute leukaemias
VAMP
Cytarabine, L-asparginase, Mtx, Doxorubicin
Hodgin’s Disease
MOPP
Bleomycine, Procarbazine, lomustine, ifosphamide, doxorubicin
Prostate carcinoma
Flutamide+GnRH agonist
Doxorubicin, cisplatin, cyclophophamide, 5-FU
Breast carcinoma
Tamoxifen, Mtx, 5-FU
Prednisolone, Vincristine, Paclitaxel, cyclophosphamide, Mitoxantrone

40. Malignancy
First line drugs
Second line drugs
Ovarian carcinoma
Cisplatin, carboplatin, paclitaxel, cyclophosphamide, Doxorubicin
Melphalan, Chlorambucil, 5-FU, Mtx, Vincristine, Topotecan
Endometrial cancer
Progestin, tamoxifen
Doxorubicin, cisplatin
Testicular tumours
Mtx, bleomycin, etoposide, cisplatin, carboplatin
Actinomycin, ifosfamide, doxorubicin, vinblastine, melphalan
Lung cancer
Cyclophosphamide, Vincristine, Doxorubicin
Carboplatin, Mtx, Lomustine, topotecan, etoposide

41. Dealing with side effects:
EMESIS:
Mainly seen with cisplatin and other alkylating agents.
Treatment: ondansetron or granisetron can be used
Metoclopromide can also be used . But since it causes extra-pyrimidal side effects, diphenhydramine can be used instead.

42. MYELOSUPPRESSION
Removing some of the patients bone marrow prior to giving cytotoxic drugs, purging it of the cancer cells and replacing it later
Administration of Molgramostim, then harvesting stem cells from blood and multiplying them in-vitro with the relevant heomopoietic growth factors.
Introducing mutated gene into the extracted bone marrow which confers multidrug resistance so that when this marrow is replaced the normal cells remain resistant to cytotoxic drugs but the cancer cells don’t .(a possibility)

43. Newer anti cancer targets
The Ras proteins- Farnesyl transferase inhibitors are in development
Tyrosine Kinase : Agents interfering with the epidermal growth factor receptor tyrosine kinase activity can be developed.
Cyclin and cyclin dependent kinases: Flavopiridol
Telomerase inhibitors
Angiogenesis and matrix metalloproteinase inhibitors:
Cyclo-oygenase inhibitors: COX-2 is overexpressed in many cancer cells. Cox-2 inhibitor celecoxib has shown to reduce mammary tumours in animal models.
P53 gene: cancer cells carry a mutated p53 gene
Antisense oligonucleotides: inhibit gene expression in tumour cells.Example : augmerosen downregulates Bcl-2

44. REFERENCES:
Rang HP, Dale MM, Ritter JM, Moore PK Pharmacology. 5th edition. New Delhi: Elsevier publication; 2002, p
Joel HG, Lee LE, Gilmann Ag. Goodmann and Gillmann’s The pharmacological basis of Therapeutics. 11th edition.Mc-Graw-Hill publication; 2006, p
Tripathi KD, Essentials of Medical Pharmacology. 6th edition. Jaypee Brothers Medical Publishers(P)LTD; 2008, p.: