1. Antineoplastic Agents
Pharmacology of
Antineoplastic Agents
Overall, I have divided this lecture into two major parts. First, some general info. In the second part, we I will talk about cellular and molecular mechanisms of action of a few select
Antineoplastic compounds. Most important part of this lecture is the mechanism of action and side effects.
Dr. Syed Mohammed Basheeruddin Asdaq, Ph.D

2. CONTENTS Background Antineoplastic Agents: classification
a. Cell Cycle Specific (CCS) agents
b. Cell Cycle Non-Specific (CCNS) agents
c. Miscellaneous (e.g., antibodies) agents
Mechanisms of action
Side Effects
Drug Resistance

3. PART I Background Antineoplastic Agents
a. Cell Cycle Specific (CCS) agents
b. Cell Cycle Non-Specific (CCNS) agents
c. Miscellaneous (e.g., antibodies) agents
Before going into mechanisms of action, we will look at some basics.

4. Cancer
Definition:
Cancer* is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems, this process is called metastasis.
Categorized based on the functions/locations of the cells from which they originate:
Carcinoma - skin or in tissues that line or cover internal organs. E.g., Epithelial cells % reported cancer cases are carcinomas.
Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.
Leukemia - White blood cells and their precursor cells such as the bone marrow cells, causes large numbers of abnormal blood cells to be produced and enter the blood.
Lymphoma - cells of the immune system that affects lymphatic system.
Myeloma - B-cells that produce antibodies- spreads through lymphatic system.
Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord.
In the next slide, we will look at the old and new ways to treat cancer.
(*National Cancer Institute, NCI)

5. THE PATHOGENESIS OF CANCER
To understand the action and drawbacks of current anticancer drugs and how drugs now in the pipeline and future agents will act, it is important to consider in more detail the pathobiology of this disease.
Cancer cells manifest, to varying degrees, four characteristics that distinguish them from normal cells:
uncontrolled proliferation
dedifferentiation and loss of function
invasiveness
metastasis.

6. THE GENESIS OF A CANCER CELL
A normal cell turns into a cancer cell because of one or more mutations in its DNA, which can be inherited or acquired.
The development of cancer is a complex multistage process, involving not only more than one genetic change but usually also other, epigenetic factors (hormonal action, co-carcinogen and tumour promoter effects, etc.) that are not in themselves cancer producing but which increase the likelihood that the genetic mutation(s) will result in cancer.
There are two main categories of genetic change that lead to cancer:
the activation of proto-oncogenes to oncogenes
the inactivation of tumour suppressor genes.

7. Activation of proto-oncogenes to oncogenes
These changes are a result of point mutations, gene amplification or chromosomal translocation, often due to the action of certain viruses or chemical carcinogens.
Activation of proto-oncogenes to oncogenes
Proto-oncogenes are genes that normally control cell division, apoptosis and differentiation but which can be converted to oncogenes by viral or carcinogen action.

8. Inactivation of tumour suppressor genes
Normal cells contain genes that have the ability to suppress malignant change-termed tumour suppressor genes (anti-oncogenes)-and there is now good evidence that mutations of these genes are involved in many different cancers.
The loss of function of tumour suppressor genes can be the critical event in carcinogenesis.
About 30 tumour suppressor genes and 100 dominant oncogenes have been identified.

9. Surgery Radiation Chemotherapy
Cancer Therapeutic Modalities (classical)
Surgery
Radiation
Chemotherapy
1/3 of patients without metastasis
Respond to surgery and radiation.
If diagnosed at early stage,
close to 50% cancer
could be cured.
50% patients will undergo chemotherapy,
to remove micrometastasis. However,
chemotherapy is able to cure only about 10-15%
of all cancer patients.
1. 30% of patients respond to surgery and radiation. 2. If diagnosed early, 50% cancer could be cured. 3. Although, 50% of the patients undergo chemotherapy, only 10-15% patients respond to chemotherapy.
In the next slide, we will look at the background of cancer chemotherapy.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

10. New types of cancer treatment
Hormonal Treatments: These drugs are designed to prevent cancer cell growth by preventing the cells from receiving signals necessary for their continued growth and division. E.g., Breast cancer – tamoxifen after surgery and radiation
Specific Inhibitors: Drugs targeting specific proteins and processes that are limited primarily to cancer cells or that are much more prevalent in cancer cells.
Antibodies: The antibodies used in the treatment of cancer have been manufactured for use as drugs. E.g., Herceptin, avastin
Biological Response Modifiers: The use of naturally occuring, normal proteins to stimulate the body's own defenses against cancer. E.g., Abciximab, rituxmab
Vaccines: Stimulate the body's defenses against cancer. Vaccines usually contain proteins found on or produced by cancer cells. By administering these proteins, the treatment aims to increase the response of the body against the cancer cells.
This slide is for your information only. We are not going to cover these agents here. But I thought, you should be aware of the new developments.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

11. Cancer Chemotherapy (Background)
Most of the recent progress using antineoplastic therapy is based on:
Development of new combination therapy of using existing drugs.
Better understanding of the mechanisms of antitumor activity.
Development of chemotherpeutic approaches to destroying micrometastases
Understanding the molecular mechanisms concerning the initiation of tumor growth and metastasis.
Recognition of the heterogeneity of tumors
B. Recently developed principles which have helped guide the treatment of neoplastic disease
A single clonogenic cell can produce enough progeny to kill the host.
2. Unless few malignant cells are present, host immune mechanisms do not play a significant role in therapy of neoplastic disease.
3. A given therapy results in destruction of a constant percentage as opposed to a constant number of cells, therefore, cell kill follows first order kinetics.

12. Cancer Chemotherapy
C. Malignancies which respond favorably to chemotherapy:
choriocarcinoma,
Acute leukemia,
Hodgkin's disease,
Burkitt's lymphoma,
Wilms' tumor,
Testicular carcinoma,
Ewing's sarcoma,
Retinoblastoma in children,
Diffuse histiocytic lymphoma and
Rhabdomyosarcoma.
D. Antineoplastic drugs are most effective against rapidly dividing tumor cells.

13. LD50 ----- Therapeutic Index = ED50
E. The Main Goal of Antineoplastic Agents
IS to eliminate the cancer cells without affecting normal tissues (the concept of differential sensitivity).  In reality, all cytotoxic drugs affect normal tissues as well as malignancies - aim for a favorable therapeutic index (therapeutic ratio).
Therapeutic Index =
LD50
-----
ED50
A therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50).
Cancer Chemotherapy
Chapter 55. B.G. Katzung

14. Infrequent scheduling of
treatment courses.
Prolongs survival but does not cure.
More intensive and
frequent treatment.
Kill rate > growth rate.
Untreated patients
F. The effects of tumor burden, scheduling, dosing, and initiation/duration of treatment on patient survival.
Early surgical removal of the primary tumor decreases the tumor burden. Chemotherapy will remove persistant secondary tumors.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

15. General rules of chemotherapy
Aggressive high-dose chemotherapy
Dose- limiting is toxicity towards normal cells
Cyclic regimens - repeated administrations with appropriate intervals for regeneration of normal cells (e.g., bone marrow cells)
Supportive therapy - to reduce toxicity
hematotoxicity – bone marrow transplantation, hematopoietic growth factors
Specific antagonists: antifolate (methotrexate) – folate (leucovorin)
MESNA - donor of –SH groups, decreased urotoxicity of cyclophosphamide. Detoxifying agent.
dexrazoxane: chelates iron, reduced anthracycline cardiotoxicity
amifostine: reduces hematotoxicity, ototoxicity and neurotoxicity of alkylating agents
MESNA is an adjuvant used in cancer chemotherapy involving cyclophosphamide and ifosfamide. It is marketed by Baxter as Uromitexan and Mesnex. MESNA is an acronym for 2-MercaptoEthane Sulfonate sodium(NA). It is a detoxifying agent.
Amifostine is a cytoprotective adjuvant used in cancer chemotherapy involving DNA-binding chemotherapeutic agents. Also commonly known as WR-1065 in its active form. It is marketed by MedImmune under the trade name Ethyol.
Dexrazoxane is used to protect the heart against the cardiotoxic side effects of anthracyclines, such as doxorubicin.
Amifostine is used therapeutically to reduce the incidence of neutropenia-related fever and infection induced by DNA-binding chemotherapeutic agents including alkylating agents (e.g. cyclophosphamide) and platinum-containing agents (e.g. cisplatin). It is also used to decrease the cumulative nephrotoxicity associated with platinum-containing agents. Amifostine is also indicated to reduce the incidence of xerostomia in patients undergoing radiotherapy for head and neck cancer.

16. General rules of chemotherapy
Combination of several drugs with different mechanisms of action, different resistance mechanisms, different dose-limiting toxicities.
Adjuvant therapy: Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.
Neoadjuvant therapy: Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery, is given. Examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy. It is a type of induction therapy.

17. General rules of chemotherapy
Supportive therapy:
-Antiemetics (5-HT3 -antagonists)
-Antibiotic prophylaxis and therapy (febrile neutropenia)
-Prophylaxis of urate nephropathy (allopurinol)
-Enteral and parenteral nutrition
-Pain – analgesic drugs
-Psychological support
There are many anti-cancer compounds. How can we classify them? Let’s look at them.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

18. Antineoplastic Agents
Alkylating agents
Topoisomerase inhibitors
Antimetabolites
Molecularly targeted
busulfan
dactinomycin
cytarabine
erlotinib
carboplatin
daunomycin
clofarabine
imatinib
carmustine
doxorubicin
fludarabine
sorafenib
cisplatin
etoposide
gemcitabine
sunitinib
cyclophosphamide
etoposide phosphate
mercaptopurine
tretinoin
dacarbazine
idarubicin
methotrexate
Herceptin
ifosfamide
irinotecan
nelarabine
Miscellaneous
lomustine
liposomal daunomycin
thioguanine
arsenic trioxide
mechlorethamine
liposomal doxorubicin
Tubulin binders
asparaginase
melphalan
mitoxantrone
docetaxel
bleomycin
oxaliplatin
teniposide
ixabepilone
dexamethasone
procarbazine
topotecan
vinblastine
hydroxyurea
temozolomide
vincristine
mitotane
thiotepa
vinorelbine
PEG-asparaginase
paclitaxel
prednisone
Here is a list of antineoplastic agents. By no means it is complete list. In the next slide, we will look at how these compounds may invade tumor cells.

19. Chemotherapy: classification based on the
mechanism of action
Antimetabolites: Drugs that interfere with the formation of key biomolecules including nucleotides, the building blocks of DNA.
Genotoxic Drugs: Drugs that alkylate or intercalate the DNA causing the loss of its function.
Plant-derived inhibitors of mitosis: These agents prevent proper cell division by interfering with the cytoskeletal components that enable the cell to divide.
Plant-derived topoisomerase inhibitors: Topoisomerases unwind or religate DNA during replication.
Other Chemotherapy Agents: These agents inhibit cell division by mechanisms that are not covered in the categories listed above.
All these agents could be either cell cycle specific or cell cycle non specific anti-neoplastic agents.

20. In next slides we are going to look at mechanism of action of alkylating agents.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

21. Cell cycle specificity of Anti-Neoplastic Agents
Vincristine,
Vinblastine
Paclitaxel, Docetaxel
Cyclophosphamide
Bleomycin
Actinomycin D M G
resting G G
Hydrocortisone 2 1
G0 = resting phase
G1 = pre-replicative phase
G2 = post-replicative phase
S = DNA synthesis
M = mitosis or cell division
In next slides we are going to look at mechanism of action of alkylating agents. S
Actinomycin D
Purine antagonists
5-Fluorouracil
Methotrexate
Cytosine arabinoside
Cyclophosphamide
Methotrexate
5-Fluorouracil
6-Mercaptopurine
Cytosine arabinoside
6-Thioguanine
Daunomycin

22. PART II Mechanisms of action Side Effects Drug Resistance
Pharmacology of Antineoplastic Agents
PART II
Mechanisms of action
Side Effects
Drug Resistance
In next slides we are going to look at mechanism of action of alkylating agents.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

23. Chemotherapy: Mechanisms of Action1
Asparaginase
Tubulin binders
Alkylating agents
Topoisomerase Inh.
Antimetabolites
DNA
Purines and
Pyrimidines
RNA
In next slides we are going to look at mechanisms of action of alkylating agents.
Protein
tubulin
Cancer Chemotherapy
Chapter 55. B.G. Katzung

24. Major Clinically Useful Alkylating Agents
Cancer Chemotherapy
Chapter 55. B.G. Katzung
Bis(mechloroethyl)amines
Nitrosoureas
Aziridines

25. An Example of DNA Crosslinking
Crosslinking: Joining two or more molecules by a covalent bond. This can either occur in the same strand (intrastrand crosslink) or in the opposite strands of the DNA (interstrand crosslink). Crosslinks also occur between DNA and protein. DNA replication is blocked by crosslinks, which causes replication arrest and cell death if the crosslink is not repaired.

26. Alkylating Agents (Covalent DNA binding drugs)
The first class of chemotherapy agents used.
They stop tumour growth by cross-linking guanine nucleobases in DNA double-helix strands - directly attacking DNA.
This makes the strands unable to uncoil and separate.
As this is necessary in DNA replication, the cells can no longer divide.
Cell-cycle nonspecific effect
Alkylating agents are also mutagenic and carcinogenic
Cancer Chemotherapy
Chapter 55. B.G. Katzung

27. E.g., Mechlorethamine (Nitrogen Mustards)
Cancer Chemotherapy
Chapter 55. B.G. Katzung

28. Cyclophosphamide
Cyclophosphamide is an alkylating agent. It is a widely used as a DNA crosslinking and cytotoxic chemotherapeutic agent.
It is given orally as well as intravenously with efficacy.
It is inactive in parent form, and must be activated to cytotoxic form by liver CYT450 liver microsomaal system to 4-Hydroxycyclophamide and Aldophosphamide.
4-Hydroxycyclophamide and Aldophosphamide are delivered to the dividing normal and tumor cells.
Aldophosphamide is converted into acrolein and phosphoramide mustard.
They crosslink DNAs resulting in inhibition of DNA synthesis .

29. Cyclophosphamide Metabolism
Inactive
Cyclophosphamide is a widely used alkylating agent. It is given orally as well as intravenously. It is inactive in parent form, and must be activated to cytotoxic form by liver CYT Hydroxycyclophamide and Aldophosphamide are delivered to the normal as well as tumor cells. Aldophosphamide is converted into acrolein and phosphoramide mustard. They crosslink DNAs resulting in inhibition of DNA synthesis.

30. Clinical Applications: Breast Cancer Ovarian Cancer
Cyclophosphamide
Clinical Applications:
Breast Cancer
Ovarian Cancer
Non-Hodgkin’s Lymphoma
Chronic Lymphocytic Leukemia (CLL)
Soft tissue sarcoma
Neuroblastoma
Wilms’ tumor
Rhabdomyosarcoma
Cyclophosphamide is a widely used alkylating agent. It is given orally as well as intravenously. It is inactive in parent form, and must be activated to cytotoxic form by liver CYT Hydroxycyclophamide and Aldophosphamide are delivered to the normal as well as tumor cells. Aldophosphamide is converted into acrolein and phosphoramide mustard. They crosslink DNAs resulting in inhibition of DNA synthesis.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

31. Depression of blood cell counts Bleeding Alopecia (hair loss)
Cyclophosphamide
Major Side effects
Nausea and vomiting
Decrease in PBL count
Depression of blood cell counts
Bleeding
Alopecia (hair loss)
Skin pigmentation
Pulmonary fibrosis
Nausea and vomiting, decrease in PBL count, BM depression, bleeding, alopecia, skin pigmentation, pulmonary fibrosis
Cancer Chemotherapy
Chapter 55. B.G. Katzung

32. Ifosphamide Mechanisms of Action Similar to cyclophosphamide
Application
Germ cell cancer,
Cervical carcinoma,
Lung cancer
Hodgkins and non-Hodgkins lymphoma
Sarcomas
Major Side Effects
Nausea and vomiting, decrease in PBL count, BM depression, bleeding, alopecia, skin pigmentation, pulmonary fibrosis

33. A. Alkylating agents 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
Cancer Chemotherapy
Chapter 55. B.G. Katzung

34. A. Alkylating agents 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

35. A. Alkylating agents 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.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

36. Summary
Cancer Chemotherapy
Chapter 55. B.G. Katzung

37. Tubulin Binding Agents
e.g., Vincristine, Vinblastine, Vindesine Vinorelbine: Inhibition of mitotic spindle formation by binding to tubulin.
M-phase of the cell cycle.
Polymerization
Vincristine 
tubulin a
e.g., Paclitexal: binds to tubulin, promotes microtubule formation
and retards disassembly; results in mitotic arrest.
Depolymerization
Paclitexal (taxol)

38. B. Natural Products 1. Antimitotic Drugs 2. Antimitotic Drugs
1. Mechanism of Action
2. Clinical application
3. Route
4. Side effects
A. Vincristine
Cytotoxic: Inhibition of mitotic spindle formation by binding to tubulin.
M-phase of the cell cycle.
Metastatic testicular cancer, Hodgkins and non-Hodgkins lymphoma, Kaposi’s sarcoma, breast carcinoma, chriocarcinoma, neuroblastoma
I.V.
Bone marrow depression, epithelial ulceration, GI disturbances, neurotoxicity
B. Vinblastine
Methylates DNA and inhibits DNA synthesis and function
Hodgkins and non-Hodgkins lymphoma, brain tumors, breast carcinoma, chriocarcinoma, neuroblastoma
Nausea and vomiting, neurotoxicity, thrombocytosis, hyperuricemia.
2. Antimitotic Drugs
1. Mechanism of Action
2. Clinical application
3. Route
4. Side effects
Paclitaxel (Taxol)
Cytotoxic: binds to tubulin, promotes microtubule formation and retards disassembly; mitotic arrest results
Melanoma and carcinoma of ovary and breast
I.V.
Myelodepression and neuropathy
In next slide we will compare how Vincristine and Paclitexal act on one of the major components of mitotic apparatus.

39. Etoposide acts primarily in the G2 and S phases of the cell cycle
3. Epipodophyllotoxins (These are CCS)
Act on Topoisomerase II
1. Mechanism of Action
2. Clinical application
3. Route
4. Side effects
A. Etoposide
Binds to and inhibits Topoisomerase II and its function. Fragmentation of DNA leading to cell death, apoptosis.
Testicular cancer, small-cell lung carcinoma, Hodgkin lymphoma, carcinoma of breast, Kaposi’s sarcoma associated with AIDS
I.V.
Myelosuppression, alopecia
B. Teniposide
Same as above
Refractory acute lymphocytic leukemia
Myelosuppression,
Accumulation of single- or double-strand DNA breaks, the inhibition of DNA replication and transcription, and apoptotic cell death.
A semisynthetic derivative of podophyllotoxin, a substance extracted from the mandrake root Podophyllum peltatum. Possessing potent antineoplastic properties, etoposide binds to and inhibits topoisomerase II and its function in ligating cleaved DNA molecules, resulting in the accumulation of single- or double-strand DNA breaks, the inhibition of DNA replication and transcription, and apoptotic cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.
Etoposide acts primarily in the G2 and S phases of the cell cycle

40. Inhibit DNA and RNA syntheses
4. Antibiotics (CCS)
1. Mechanism of Action
2. Clinical application
3. Route
4. Side effects
a. Dactinomycin (ACTINOMYCIN D)
It binds to DNA and inhibits RNA synthesis, impaired mRNA production, and protein synthesis
Rhabdomyosarcoma and Wilm's tumor in children;
choriocarcinoma (used with methotrexate
I.V.
Bone marrow depression, nausea and vomiting, alopecia,
GI disturbances, and ulcerations of oral mucosa
b. Daunorubicin
(CERUBIDIN)
Doxorubicin
(ADRIAMYCIN)
inhibit DNA and RNA synthesis
Acute lymphocytic/granulocytic leukemias; treatment of
choice in nonlymphoblastic leukemia in adults when
given with cytarabine
Side effects: bone marrow depression, GI disturbances and cardiac toxicity (can be prevented by dexrazoxane)
Acute leukemia, Hodgkin's disease, non Hodgkin's
lymphomas (BACOP regimen), CA of breast & ovary,
small cell CA of lung, sarcomas, best available agent
for metastatic thyroid CA
Cardiac toxicity, Doxorubicin mainly affects the heart muscles, leading to tiredness or breathing trouble when climbing stairs or walking, swelling of the feet .
c. Bleomycin (BLENOXANE)
fragment DNA chains and inhibit repair
Germ cell tumors of testes and ovary, e.g., testicular
carcinoma (can be curative when used with vinblastine & cisplatin), squamous cell carcinoma
Given I.V. or I.M.
Mucosocutaneous reactions and pulmonary fibrosis; bone
marrow depression much less than other antineoplastics
Inhibit DNA and RNA syntheses
Cancer Chemotherapy
Chapter 55. B.G. Katzung

41. 5. Enzymes: L-asparaginase
1. Mechanism of Action
2. Clinical application
3. Route
4. Side effects
L-asparaginase
Hydrolyzes L-asparagine (to L-aspartic acid) an essential amino acid to many leukemic cells
Acute lymphocytic leukemia, induction of remission in acute lymphoblastic leukemia when
combined with vincristine, prednisone, and anthracyclines
I.V. or I.M.
Nausea and vomiting, Poor appetite, Stomach cramping, Mouth sores, Pancreatitis. Less common: blood clotting
Cancer Chemotherapy
Chapter 55. B.G. Katzung

42. * * * * * C. Antimetabolites MTX Kills cells during S-phase
MTX polyglutamates
Are selectively retained
In tumor cells.
C. Antimetabolites
(Folic acid analog)
Folic acid is a growth factor that provides single carbons to the precursors used to form the nucleotides used in the synthesis of DNA and RNA. To function as a cofactor folate must be reduced by DHFR to THF.
Reduced
Folate
Carrier
protein * * * * *
Methotrexate (MTX) is a folic acid analog that binds with active site of DHFR, interfering with synthesis of tetrahydrofolate (THF), which serves as the key one-carbon carrier for enzymatic processes for involved in de novo synthesis of thymidylate, purine nucleotides, and amino acid serine and methionine.
MTX
Kills cells during
S-phase
Cancer Chemotherapy
Chapter 55. B.G. Katzung

43. inhibits formation of FH4 (tetrahydrofolate) from folic
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.
Methotrexate (MTX) is a folic acid analog that binds with active site of DHFR, interfering with synthesis of tetrahydrofolate (THF), which serves as the key one-carbon carrier for enzymatic processes for involved in de novo synthesis of thymidylate, purine nucleotides, and amino acid serine and methionine.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

44. 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
2 Purine analogs:
6-Mercaptopurine (6-MP) and Thioguanine
Blocks DNA synthesis by inhibiting conversion of
IMP to AMPS and to XMP as well as blocking conversion of AMP to
ADP; also blocks first step in purine synthesis.
Feedback inhibition
blocks DNA synthesis by inhibiting conversion of IMP to
XMP as well as 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,

45. 6. Drug Resistance
One of the fundamental issue in cancer chemotherapy is the development of cellular drug resistance. It means, tumor cells are no longer respond to chemotherapeutic agents. For example, melanoma, renal cell cancer,
brain cancer often become resistant to chemo.
A few known reasons:
Mutation in p53 tumor suppressor gene occurs in 50% of all tumors. This leads to resistance to radiation therapy and wide range of chemotherapy.
Defects or loss in mismatch repair (MMR) enzyme family. E.g., colon cancer no longer respond to fluoropyrimidines, the thiopurines, and cisplatins.
Increased expression of multidrug resistance MDR1 gene which encodes P-glycoprotein resulting in enhanced drug efflux and reduced intracellular accumulation. Drugs such as athracyclines, vinca alkaloids, taxanes, campothecins, even antibody such as imatinib.
Cancer Chemotherapy
Chapter 55. B.G. Katzung

46. Summary
The main goal of anti-neoplastic drug is to eliminate the cancer cells without affecting normal tissues.
Log-Kill Hypothesis states that a given therapy kills a percentage of cells, rather then a constant number, therefore, it follows first order kinetics. Aim for a favorable therapeutic index.
Early diagnosis is the key.
Combination therapy and adjuvant chemotherapy are effective for small tumor burden.
Two major classes of antineoplastic agents are:
a. Cell Cycle Specific and
b. Cell Cycle Non-Specific agents
Because chemotherapeutic agents target not only tumor cells, but also affect normal dividing cells including bone marrow, hematopoietic, and GI epithelium. Know what the side effects are.
Drug resistance is often associated with loss of p53 function, DNA mismatch repair system, and increased MDR1 gene expression.
Surgery then chemotherapy is adjuvant