Anticancer Drugs In Depth 1. Q: What is the ultimate goal of cancer chemotherapy?

1. Q: What is the ultimate goal of cancer chemotherapy?

A: Cure = eradication of every neoplastic cell and long-term disease-free survival. If cure isn't possible, goals are disease control or palliation.

2. Q: What is adjuvant chemotherapy?

A: Chemotherapy after surgery/radiation to eradicate micrometastases.

3. Q: What is neoadjuvant chemotherapy?

A: Chemotherapy before surgery to shrink the tumor.

4. Q: What is maintenance chemotherapy?

A: Lower-dose therapy used to prolong remission.

5. Q: Why is combination chemotherapy generally superior to single-agent therapy?

A: It:

• Maximizes tumor-cell killing.

• Targets heterogeneous tumor cell populations.

• Delays/prevents resistance.

• Can combine drugs with nonoverlapping toxicities.

6. Q: Which tumor cells are generally most sensitive to chemotherapy?

A: Rapidly dividing cells with a high growth fraction.

7. Q: What happens to nondividing cells in G0?

A: They are generally less susceptible to many chemotherapeutic agents.

8. Q: Which drugs are cell-cycle specific?

A: Primarily antimetabolites, vinca alkaloids, and taxanes.

9. Q: Which major class is cell-cycle nonspecific?

A: Alkylating agents.

10. Q: What is the log-kill phenomenon?

A: A given dose of chemotherapy kills a constant fraction, not a constant number, of tumor cells.

Example: a 5-log kill = 99.999% reduction.

11. Q: Why may CNS tumors/leukemia require intrathecal chemotherapy?

A: The blood-brain barrier creates a pharmacologic sanctuary that prevents adequate penetration of some systemic drugs.

12. Q: What is primary vs acquired chemotherapy resistance?

A:

• Primary resistance: tumor never responds.

• Acquired resistance: tumor initially responds but later becomes resistant.

13. Q: What is multidrug resistance (MDR)?

A: Resistance caused in part by increased expression of P-glycoprotein, an ATP-dependent drug efflux pump.

14. Q: What is the clinical consequence of P-glycoprotein overexpression?

A: Decreased intracellular concentration of multiple structurally unrelated drugs → multidrug resistance.

15. Q: How can chemotherapy resistance be minimized?

A: Short, intensive, intermittent combination therapy using drugs with different mechanisms.

16. Q: Why do traditional chemotherapy drugs cause mucositis, alopecia, and myelosuppression?

A: They attack rapidly proliferating normal cells in:

• Bone marrow

• GI mucosa

• Buccal mucosa

• Hair follicles

17. Q: What is the major dose-limiting toxicity of many chemotherapy drugs?

A: Myelosuppression, especially neutropenia.

18. Q: What is tumor lysis syndrome?

A: Massive tumor-cell destruction → release of intracellular contents.

Classic findings:

• ↑ K⁺

• ↑ uric acid

• ↑ phosphate

• ↓ Ca²⁺

19. Q: Which tumors are particularly associated with tumor lysis syndrome?

A: Highly proliferative/highly chemotherapy-sensitive tumors, especially Burkitt lymphoma and T-cell ALL.

20. Q: What can be used to reduce chemotherapy-induced neutropenia?

A: Granulocyte colony-stimulating factors (G-CSF).

21. Q: What is the mechanism of methotrexate?

A: Inhibits dihydrofolate reductase (DHFR) → ↓ tetrahydrofolate → ↓ nucleotide synthesis → impaired DNA synthesis.

22. Q: What cell-cycle phase is methotrexate specific for?

A: S phase.

23. Q: What is the rescue drug for high-dose methotrexate toxicity?

A: Leucovorin (folinic acid).

24. Q: Why does leucovorin rescue methotrexate toxicity?

A: It bypasses DHFR and replenishes reduced folate.

25. Q: What is an important renal toxicity of high-dose methotrexate?

A: Crystalluria/renal toxicity from poorly soluble metabolites.

26. Q: How can methotrexate renal toxicity be reduced?

A: Hydration + urine alkalinization + leucovorin rescue when appropriate.

27. Q: What are important clinical uses of methotrexate?

A: ALL, Burkitt lymphoma, breast cancer, head/neck cancers, mycosis fungoides; also inflammatory diseases such as RA and psoriasis.

28. Q: How does pemetrexed differ from methotrexate?

A: It inhibits DHFR plus thymidylate synthase and other folate-dependent enzymes.

29. Q: What is pemetrexed mainly used for?

A: Lung cancer, particularly nonsquamous NSCLC.

30. Q: What supplementation is given with pemetrexed?

A: Folic acid + vitamin B12; corticosteroid pretreatment helps prevent cutaneous reactions.

31. Q: What is pralatrexate used for?

A: Relapsed/refractory T-cell lymphoma.

32. Q: What is 6-mercaptopurine (6-MP)?

A: A purine antimetabolite that becomes activated intracellularly and interferes with DNA/RNA synthesis.

33. Q: What is the classic use of 6-MP?

A: Maintenance therapy for ALL.

34. Q: What important drug is converted to 6-MP?

A: Azathioprine.

35. Q: What is fludarabine used to treat?

A: CLL, hairy cell leukemia, and indolent non-Hodgkin lymphoma.

36. Q: What is the key mechanism of fludarabine?

A: Purine analog incorporated into DNA/RNA → inhibits nucleic acid synthesis.

37. Q: What is the mechanism of 5-FU?

A: Converted to 5-FdUMP, which inhibits thymidylate synthase → ↓ dTMP → impaired DNA synthesis.

38. Q: What cell-cycle phase is 5-FU specific for?

A: S phase.

39. Q: What is the classic clinical use of 5-FU?

A: Colorectal and other solid tumors, including breast, gastric, pancreatic, and ovarian cancers.

40. Q: Why is leucovorin combined with 5-FU?

A: It stabilizes the 5-FdUMP–thymidylate synthase complex, increasing 5-FU activity.

41. Q: What enzyme deficiency can cause severe 5-FU toxicity?

A: Dihydropyrimidine dehydrogenase (DPD) deficiency.

42. Q: What are major toxicities of 5-FU in DPD deficiency?

A: Severe mucositis, diarrhea, and pancytopenia.

43. Q: What is capecitabine?

A: An oral prodrug of 5-FU.

44. Q: What is a hallmark toxicity of capecitabine?

A: Hand-foot syndrome.

45. Q: Why is capecitabine relatively tumor-selective?

A: Its final conversion to 5-FU is mediated by thymidine phosphorylase, which is concentrated in tumors.

46. Q: What is cytarabine's mechanism?

A: Pyrimidine analog converted to ara-CTP, which inhibits DNA polymerase and can terminate DNA chain elongation.

47. Q: What cell-cycle phase is cytarabine specific for?

A: S phase.

48. Q: What is the major use of cytarabine?

A: AML.

49. Q: Why can cytarabine be given intrathecally?

A: Systemic administration does not achieve sufficient CNS penetration.

50. Q: What is gemcitabine?

A: A deoxycytidine analog that inhibits DNA synthesis after intracellular phosphorylation.

51. Q: What cancers are classically associated with gemcitabine?

A: Pancreatic cancer and NSCLC.

52. Q: What are the major anthracyclines?

A: Doxorubicin, daunorubicin, idarubicin, epirubicin.

53. Q: What are the major mechanisms of doxorubicin?

A:

• DNA intercalation

• Topoisomerase II inhibition

• Free-radical generation

54. Q: What is the classic dose-limiting toxicity of doxorubicin?

A: Irreversible cardiotoxicity → dilated cardiomyopathy/heart failure.

55. Q: What should be monitored during doxorubicin therapy?

A: Left ventricular ejection fraction (LVEF).

56. Q: What drugs can reduce doxorubicin cardiotoxicity?

A: Dexrazoxane and liposomal doxorubicin formulations.

57. Q: What is a classic administration danger with doxorubicin?

A: Extravasation → severe tissue necrosis.

58. Q: What is a memorable harmless effect of anthracyclines?

A: Red urine due to the drug's red color.

59. Q: What is bleomycin's mechanism?

A: Generates free radicals → DNA strand breaks.

60. Q: What phase is bleomycin most associated with?

A: G2 phase.

61. Q: What are the classic uses of bleomycin?

A: Testicular cancer and Hodgkin lymphoma.

62. Q: What is the hallmark toxicity of bleomycin?

A: Pulmonary fibrosis ("bleomycin lung").

63. Q: Why does bleomycin preferentially cause lung and skin toxicity?

A: These tissues have low levels of bleomycin-inactivating hydrolase.

64. Q: Is significant myelosuppression common with bleomycin?

A: No — it is relatively uncommon.

65. Q: What is the basic mechanism of alkylating agents?

A: Covalently modify DNA, especially nucleophilic sites → DNA cross-linking/damage → cell death.

66. Q: Are alkylating agents cell-cycle specific?

A: No. They can act in both cycling and resting cells.

67. Q: What long-term complication is associated with alkylating agents?

A: Secondary malignancies, particularly therapy-related leukemia.

68. Q: What activates cyclophosphamide and ifosfamide?

A: Hepatic CYP450 metabolism.

69. Q: What are the active metabolites of cyclophosphamide/ifosfamide?

A: Phosphoramide mustard = antitumor effect; acrolein = bladder toxicity.

70. Q: What is the classic toxicity of cyclophosphamide and ifosfamide?

A: Hemorrhagic cystitis.

71. Q: What causes hemorrhagic cystitis?

A: Acrolein/toxic metabolites in urine.

72. Q: How do you prevent cyclophosphamide/ifosfamide hemorrhagic cystitis?

A: Mesna + aggressive hydration.

73. Q: Which drug has an important neurotoxicity due to chloroacetaldehyde?

A: Ifosfamide.

74. Q: What is special about nitrosoureas such as carmustine and lomustine?

A: They are lipophilic and cross the blood-brain barrier.

75. Q: What are nitrosoureas primarily used for?

A: Brain tumors.

76. Q: What is the mechanism of nitrosoureas?

A: DNA alkylation + protein carbamoylation.

77. Q: What is the active metabolite of dacarbazine?

A: MTIC.

78. Q: What is dacarbazine classically used for?

A: Melanoma and Hodgkin lymphoma.

79. Q: How does temozolomide differ from dacarbazine?

A: Temozolomide does not require CYP450 activation and readily crosses the BBB.

80. Q: What is temozolomide classically used for?

A: Glioblastoma/astrocytoma and metastatic melanoma.

81. Q: What is the mechanism of cisplatin?

A: Forms DNA intra- and interstrand cross-links, especially involving guanine.

82. Q: What are the major toxicities of cisplatin?

A:

• Nephrotoxicity

• Ototoxicity

• Severe nausea/vomiting

83. Q: How is cisplatin nephrotoxicity prevented?

A: Aggressive IV hydration.

84. Q: What is the major dose-limiting toxicity of carboplatin?

A: Myelosuppression.

85. Q: Why might carboplatin be preferred over cisplatin?

A: It has substantially less nephrotoxicity, neurotoxicity, and ototoxicity, making it useful when cisplatin toxicity is a concern.

86. Q: What is the classic toxicity of oxaliplatin?

A: Cold-induced peripheral neuropathy.

87. Q: What cancer is oxaliplatin particularly associated with?

A: Colorectal cancer.

88. Q: What are the major vinca alkaloids?

A: Vincristine, vinblastine, vinorelbine.

89. Q: What is the mechanism of vinca alkaloids?

A: Bind tubulin → inhibit microtubule polymerization → mitotic spindle disruption.

90. Q: What cell-cycle phase do vinca alkaloids target?

A: M phase/metaphase.

91. Q: What is the key toxicity of vincristine?

A: Peripheral neuropathy + constipation.

92. Q: What is the key toxicity of vinblastine?

A: Myelosuppression.

93. Q: What is the key toxicity of vinorelbine?

A: Myelosuppression.

94. Q: What catastrophic medication error must be remembered with vinca alkaloids?

A: NEVER administer intrathecally. It can be fatal.

95. Q: What is the "O" in R-CHOP?

A: Oncovin = vincristine.

96. Q: What are the major taxanes?

A: Paclitaxel and docetaxel.

97. Q: How do taxanes differ from vinca alkaloids?

A:

• Vinca: prevent microtubule polymerization.

• Taxanes: promote/stabilize microtubules.

Both ultimately disrupt mitosis.

98. Q: What cell-cycle phase do taxanes target?

A: G2/M.

99. Q: What are major taxane toxicities?

A: Neutropenia/leukopenia and peripheral neuropathy.

100. Q: What is a classic adverse effect of docetaxel?

A: Severe fluid retention/edema.