Chapter 54 Cancer Chemotherapy

1. Chapter 54Cancer Chemotherapy

2. Background • It is the second most common cause of death in the developed nations • One in three people will be diagnosed with cancer during their lifetime • The terms cancer, malignant neoplasm and malignant tumour are synonymous • Both benign and malignant tumours manifest uncontrolled proliferation, but the latter are distinguished by their capacity for dedifferentiation, their invasiveness and their ability to metastasise (spread to other parts of the body

3. Background • Cancer: is a disease in which there is uncontrolled multiplication & spread within the body of abnormal forms of body’s own cells • Cancer cells manifest, to varying degrees, four characteristics that distinguish them from normal cells: • Uncontrolled proliferation • Dedifferentiation & loss of function • Invasiveness • Metastasis

4. Causes • A normal cell turns into a cancer cell b/c of one or more mutation in its DNA, which can be inherited or acquired , which can be inherited or acquired, usually through exposure to viruses or carcinogens (e.g. tobacco products, asbestos) • 2 main categories of genetic changes: • Induce of oncogenic transformation • Inactivation of tumour suppressor genes • About 30 tumour suppressor genes and 100 dominant oncogenes have been identified

5. Causes • Incidence, geographical distribution, & behaviour of specific types of cancer are related to: age, sex, race, genetic predisposition, & exposure to environmental carcinogens

7. Principles of cancer chemotherapy • Drug therapy is used in patients with cancer to: • Eradicate the disease • Induce a remission • Control symptoms • Ideal anticancer drugs would eradicate cancer cells without harming normal tissues • Unfortunately, most currently available agents do not specifically recognize neoplastic cells but affect all kind of proliferating cells

8. Principles of cancer chemotherapy • The treatment of cancer patients requires a skillfulinterdigitation of pharmacotherapy with other modalities of treatment (e.g., surgery and irradiation) • In biochemical terms, cancer cells and normal cells are so similar in most respects that it is more difficult to find general, exploitable, biochemical differences between them

9. Principles of cancer chemotherapy • Individual patient characteristics determine the choice of modalities • Not all patients can tolerate drugs, and not all drug regimens are appropriate for a given patient • Renal and hepatic function, bone marrow reserve, general performance status, and concurrent medical problems all come into consideration in making a therapeutic plan

10. Principles of Drug Treatment • The log cell kill hypothesis: cytotoxic effect of anticancer drugs follow log-cell kinetics: a given dose would be predicted to kill a constant proportion/fractionof cells • For example: if an individual drug leads to a 3 log kill of cancer cells and reduces the tumor burden from 1010 to 107 cells, the same dose used at a tumor burden of 105 cells reduces the tumor mass to 102 cells • Cell kill is, therefore, proportional, regardless of tumor burden

11. Benefits of combination therapy • Combination-drug chemotherapy is more successful than single-drug treatment in most of the cancers for which chemotherapy is effective b/c: • It provides maximal cell kill within the range of toxicity tolerated by the host for each drug • It provides a broader range of interaction between drugs and tumor cells with different genetic abnormalities in a heterogeneous tumorpopulation • It may prevent or slow the subsequent development of cellular drug resistance

12. Benefits of combination therapy • Certain principles have been used in designing such treatments • Efficacy: each drug should have some individual therapeutic activity against the particular tumor being treated • Toxicity: Drugs with different dose-limiting toxicities should be used to avoid overlapping toxicities • Optimum scheduling: Intensive intermittent schedules should allow time for recovery from the acute toxic effects, primarily bone marrow toxicity

13. Benefits of combination therapy • Drugs that act by different mechanisms may have additive or synergistic therapeutic effects. Combination therapy will thus increase log cell kill and diminish the probability of emergence of resistant clones of tumorcells • Several cycles of treatment should be given, since one or two cycles of therapy are rarely sufficient to eradicate a tumor. Most curable tumorsrequire at least six to eight cycles of therapy

14. Benefits of combination therapy • Example of combination therapy of advanced Hodgkin’s disease: • MOPP (mechlorethamine, Oncovin [vincristine sulfate], procarbazine, prednisone) • ABVD (Adriamycin [doxorubicin hydrochloride], bleomycin,vinblastine, dacarbazine), has resulted in cure rates of 50 to 60%

15. Cell-cycle specificity of drugs • Both normal cells & tumor cells go through growth cycle • The number of cells that are in various stages of the cycle may differ in the normal & neoplastic tissues • The normal cell cycle consists of a definable sequence of events that characterize the growth and division of cells

16. Cell-cycle specificity of drugs • Cell cycle specific (CCS) drugs: effective only against replicating cells (most effective against hematological malignancies & in solid tumors in which large proportion of the cells are proliferating) • Cell-cycle nonspecific (CCNS) drugs: many bind to cellular DNA. Useful against low growth and high growth tumors (e.g., carcinomas of the colon or non–small cell lung cancer)

18. Resistance • Primary resistance (inherent drug resistance): melanoma, renal cell cancer, & brain cancer • Acquired resistance: genetic mutation particularly after prolonged administration of suboptimal doses (minimized by short term, intensive, intermittent therapy administration or by drug combinations)

19. Possible mechanisms of Anticancer Drug Resistance

20. Multidrug resistance • Tumorcells may become generally resistant to a variety of cytotoxic drugs on the basis of decreased uptake or retention of the drugs • It is the major form of resistance to a broad range of structurally unrelated anticancer agents, including the anthracyclines, vinca alkaloids, taxanes, camptothecins, epipodophyllotoxins • It is associated with increased expression of the MDR1 gene, which encodes a cell surface transporter glycoprotein (P-glycoprotein)

21. Multidrug resistance • Associated with increased expression of a normal gene (the MDR1 gene) for a cell surface glycoprotein (P-glycoprotein) involved in drug efflux • Multidrug resistance can be reversed experimentally by calcium channel blockers, such as verapamil, and a variety of other drugs, which inhibit the transporter

22. The multidrug resistance gene MDR1, which encodes the cell-surface molecule P-glycoprotein (PGP), can confer resistance to a wide variety of drugs. PGP transports drugs out of the cell, which is a process that requires the presence of two ATP-binding domains. These domains are a defining characteristic of this family of ATP-binding cassette (ABC) transporters. The exact mechanism of drug efflux is not well understood, but might involve either direct transport out of the cytoplasm or redistribution of the drug as it transverses the plasma membrane. Some cytotoxic drugs that are known substrates for PGP include etoposide, daunomycin, taxol, vinblastine and doxorubicin. PGP is modified by sugar moieties (black) on the external surface of the protein

23. Toxicity of cancer chemotherapy • Most anticancer s have a narrow therapeutic index • Therapy aimed at killing rapidly dividing cancer cells also affects normal cells undergoing rapid proliferation (for example, cells of the buccal mucosa, bone marrow, gastrointestinal (GI) mucosa, and hair), contributing to the toxic manifestations of chemotherapy

24. Common ADEs • Bone marrow suppression that predisposes to infections • GIT: • N & V: phenothiazines and other centrally acting • Damage to the the GIT muycosa: stomatitis, dysphagia, and diarrhea • Alopecia • Sterility • Hyperuricemia (tumor lysis syndrome)

25. Drugs used in cancer chemotherapy • Alkylating agents and related compounds • Antimetabolites • Cytotoxic antibiotics • Plant derivatives (vinca alkaloids, taxanes, campothecins) • Hormones • Miscellaneous agents

27. ALKYLATING AGENTS • The alkylating agents are the largest class of anticancer agents • Nitrogen mustards:chlorambucil, cyclophosphamide, mechlorethamine • Nitrosureas:carmistine, lomustine • Alkylsulfonates: busulfan • Platinum analogs: cisplatin, carboplatin, and oxaliplatin • Other Alkylating Agents: dacarbazine, procarbazine, & bendamustine

28. Mechanism of actions • Form reactive molecular species/ intermediate that transfer of their alkyl groups to various cellular constituents • The macromolecular sites of alkylation damage include DNA, RNA, proteins, and various enzymes • Alkylations of DNA within the nucleus represent the major interactions that lead to cell death • The major site of alkylation within DNA is the N7 position of guanine

29. Most major alkylating agents are bifunctional, with two reactive groups

31. ALKYLATING AGENTS • Are cell cycle-nonspecific, but cells are most susceptible to alkylation in late G1 & S phases • Used in combination with other agents to treat a wide variety of lymphatic and solid cancer • Mutagenic & carcinogenic and can lead to secondary malignancies, such as acute leukemia

32. Drug resistance • Increase capability to repair DNA lesions • Decrease permeability of the cell to the alkylating agents • Increase production/activity of glutathione of glutathione S-transferase, which can conjugate with and detoxify electrophilic intermediates

33. A. Cyclophosphamide • Pro-drug that needs hepatic activation by CYP450 (4-hydroxy cyclophosphamide):The active compounds, are phosphoramide mustard and acrolein • Clinical uses: • Cyclophosphamide has a wide spectrum of antitumor activity: Breast cancer, ovarian cancer, non-Hodgkin's lymphoma, CLL, soft tissue sarcoma, neuroblastoma, Wilms' tumor, rhabdomyosarcoma • Alternative to azathioprine in suppressing immunological rejection of transplant organs

34. A. Cyclophosphamide • Specific ADE: • Hemorrhagic cystitis: Dysuria and decreased urinary frequency • Due to acrolein in the urine • Can be minimized by vigorous hydration & by use of sodium 2-mercaptoethane sulfonate (MESNA) which “traps” acrolein • Other common ADEs: • Alopecia • NVD • Bone marrow suppression

35. B. Mechlorethamine • Originally developed as a vesicant (nitrogen mustard) during world war I • IV administered • The major indication for mechlorethamineis Hodgkin’s disease; the drug is given in the MOPP regimen

36. B. Mechlorethamine • Specific ADEs: • Marked vesicant action (blistering agent): care should be taken to avoid extravasation into Sctissues or even spillage onto the skin • Reproductive toxicity includes amenorrhea and inhibition of oogenesis and spermatogenesis • Common ADEs: • Bone marrow suppression • Immunosuppression (herpes zoster infections, especially in patients with lymphomas) • Alopecia • NVD

37. C. Nitrosureas: Carmustine (IV) & Lomustine (orally) • Are highly lipid-soluble and are able to cross the BBB, making them effective in the treatment of brain tumors • Both alkylation and carbamoylationcontribute to the therapeutic and toxic effects of the nitrosoureas

38. C. Nitrosureas: Carmustine (IV) & Lomustine (orally) • ADEs: • Bone marrow depression: 4 to 5 weeks • Severe nausea and vomiting • Pulmonary toxicity, manifested by cough, dyspnea, and interstitial fibrosis (long term) • Less frequent: alopecia, stomatitis, and mild abnormalities of liver function • Potentially, mutagenic, teratogenic, and carcinogenic

39. Streptozocin (STZ) • Sugar-containing nitrosourea • It has a high affinity for cells of the islets of Langerhans & is transported into the cell by the glucose transport protein GLUT2 • Clinical use: insulin-secreting islet cell carcinoma of the pancreas • ADEs: • Abnormal glucose tolerance (hypoglycemic coma) • Renal tubular damage in 5 to 10% of patients

40. D. Platinum analogs (cisplatin, carboplatin, & oxaliplatin) • First generation: Cisplatin • Clinical uses: solid tumors (non-small cell and small cell lung cancer, esophageal and gastric cancer, head and neck cancer, and genitourinary cancers, particularly testicular, ovarian, and bladder cancer) • ADEs: • Renal toxicity (major) • N and V • Anemia: require transfusions of RBCs • Hearing loss (10 to 30% of patients)

42. D. Platinum analogs (cisplatin, carboplatin, & oxaliplatin) • Second generation: Carboplatin • MOA, mechanisms of resistance, and clinical uses are identical to cisplatin • it exhibits significantly less renal toxicity and IT toxicity, peripheral nerves, and hearing loss • It is more myelosuppressive than cisplatin • Third generation: oxaliplatin • Similar to cisplatinand carboplatin, but with significant activity against colorectal cancer • ADEs: Neurotoxicity manifested by a peripheral sensory neuropathy

43. Other Alkylating Agents • Procarbazine: • Activated by hepatic CYPs to highly reactive alkylating species that methylate DNA • Oxidative metabolism of this drug by microsomal enzymes generates azoprocarbazine and H2O2, which may be responsible for DNA strand scission • Itis commonly used in combination regimens for Hodgkin's and non-Hodgkin's lymphoma and brain tumors

44. Other Alkylating Agents • Procarbazine: • Procarbazineis a weak MAOI: hypertensive reactions may result from its use concurrently with sympathomimetic agents, TCA, or ingestion of foods with high tyraminecontent • CNS toxicity with neuropathy, ataxia, lethargy, and confusion • The carcinogenic potential of procarbazine is thought to be higher than that of most other alkylating agents

45. Other Alkylating Agents • Dacarbazine • It is used in the treatment of malignant melanoma • It is a potent vesicant, and care must be taken to avoid extravasation

46. Other alkylating agents • Dacarbazine • Temzolomide (brain tumor) • Melphalan • Chlorambucil • Busulfan • Bendamustine • Thiotepa • Altretamine

47. ANTIMETABOLITES (Structural Analogs) • Are structurally similar to endogenous compounds, such as vitamins, amino acids,and nucleotides • These drugs can compete for binding sites on enzymes or can themselves become incorporated into DNA or RNA and thus interfere with cell growth and proliferation

48. ANTIMETABOLITES (Structural Analogs) • The antimetabolites in clinical use include: • Folic acid analogues: methotrexate • Purine analogues:mercaptopurine, thioguanine • Pyrimidine analogues: fluorouracil, cytarabine • CCS drugs acting primarily in S phase • Are also used as immunosuppressants

49. Folate antagonistMethotrexate (MTX) • Folic acid is an essential dietary factor that is converted by enzymatic reduction to a series of tetrahydrofolate (FH4) cofactors that provide methyl groups for the synthesis of precursors of DNA (thymidylate and purines) and RNA (purines) • Interference with FH4 metabolism reduces the cellular capacity for one-carbon transfer and the necessary methylation reactions in the synthesis of purine ribonucleotides and thymidine monophosphate (TMP), thereby inhibiting DNA replication

50. Folate antagonistMethotrexate (MTX) • MoA: • Cellular uptake of the drug is by carrier-mediated active transport • MXT competitively inhibits the binding of folic acid to the enzyme dihydrofolatereductase (DHFR), interfering with the synthesis of tetrahydrofolate(FH4), which serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine