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🧪 Chemotherapy - Easy Notes

Source: Lippincott Illustrated Reviews: Pharmacology

1. What is Chemotherapy?

Chemotherapy uses chemical drugs to kill or slow the growth of cancer cells. It works mainly by targeting rapidly dividing cells. About 10% of cancer patients achieve cure/prolonged remission with chemo alone; in most cases it produces regression but not a cure. The overall 5-year survival for cancer patients is ~68%.

2. Key Concepts

Term	Meaning
Cell cycle specific	Drug works only in a specific phase (e.g., S phase)
Cell cycle non-specific	Drug works in any phase, including resting cells
Myelosuppression	Bone marrow suppression - most common side effect
Nadir	Lowest point of blood cell counts after chemo
Combination therapy	Multiple drugs used together to increase efficacy and reduce resistance

3. Classes of Chemotherapy Drugs

A. Alkylating / Adducting Agents

Mechanism: Cross-link DNA strands, preventing replication. Cell cycle non-specific.

Drug	Key Notes
Cyclophosphamide	Prodrug; activated by liver CYP450. Unique toxicity = hemorrhagic cystitis (prevented by Mesna + hydration)
Ifosfamide	Similar to cyclophosphamide; also causes hemorrhagic cystitis. Neurotoxicity from chloroacetaldehyde metabolite
Cisplatin / Carboplatin	Platinum compounds; cross-link DNA. Cisplatin = nephrotoxic + ototoxic; carboplatin = less toxic
Carmustine / Lomustine (Nitrosoureas)	Penetrate the CNS - used for brain tumors. Delayed myelosuppression (4-6 weeks)
Busulfan	Used in CML and bone marrow transplant prep. Causes pulmonary fibrosis

Mnemonic: "Alkylating agents CROSS the DNA bridge"

B. Antimetabolites

Mechanism: Mimic normal building blocks of DNA/RNA; block their synthesis. Cell cycle specific - S phase.

Drug	Class	Key Notes
Methotrexate (MTX)	Folate analog	Inhibits DHFR. Toxicity rescued by leucovorin. Nephrotoxic at high doses
5-Fluorouracil (5-FU)	Pyrimidine analog	Inhibits thymidylate synthase. Side effect: hand-foot syndrome, mucositis
Capecitabine	Pyrimidine analog	Oral prodrug of 5-FU. Also causes hand-foot syndrome
6-Mercaptopurine (6-MP)	Purine analog	Reduce dose by 50-75% with allopurinol (to prevent toxicity)
Cytarabine (Ara-C)	Pyrimidine analog	Used in leukemias. High-dose causes cerebellar toxicity
Gemcitabine	Pyrimidine analog	Used in pancreatic, lung, bladder cancer
Fludarabine	Purine analog	Used in CLL. Causes immunosuppression

Mnemonic: "Antimetabolites are Fake Nucleotides"

C. Antibiotics (Antitumor)

Mechanism: Intercalate DNA, generate free radicals, inhibit topoisomerase II.

Drug	Key Notes
Doxorubicin (Adriamycin)	Most widely used. Causes cardiomyopathy (dose-dependent); use dexrazoxane for cardiac protection
Bleomycin	Causes pulmonary fibrosis (unique lung toxicity). Used in testicular cancer, Hodgkin lymphoma
Daunorubicin	Used in AML/ALL; also cardiotoxic

D. Plant Alkaloids

Vinca Alkaloids (from periwinkle plant)

Mechanism: Bind tubulin, prevent spindle formation → cell arrest in M phase.

Drug	Key Notes
Vincristine	Peripheral neuropathy (dose-limiting). Minimal myelosuppression
Vinblastine	Myelosuppression (dose-limiting). Less neuropathy

Taxanes

Mechanism: Stabilize microtubules (prevent disassembly) → block mitosis.

Drug	Key Notes
Paclitaxel (Taxol)	Used in breast, ovarian, lung cancer. Causes peripheral neuropathy, hypersensitivity
Docetaxel	Similar to paclitaxel

Topoisomerase Inhibitors

Drug	Type	Key Notes
Etoposide (VP-16)	Topo II inhibitor	Used in lung cancer, lymphoma
Irinotecan / Topotecan	Topo I inhibitors (Camptothecins)	Diarrhea is dose-limiting side effect

E. Hormonal Agents

Used mainly in hormone-sensitive cancers (breast, prostate).

Drug	Mechanism	Use
Tamoxifen	SERM - blocks estrogen receptors	ER+ breast cancer
Letrozole / Anastrozole	Aromatase inhibitors	Post-menopausal breast cancer
Leuprolide / Goserelin	GnRH agonists (cause hormone ablation)	Prostate cancer
Flutamide / Bicalutamide	Androgen receptor blockers	Prostate cancer

F. Targeted Therapy

Monoclonal Antibodies (end in -mab)

Drug	Target	Use
Trastuzumab (Herceptin)	HER2/neu	HER2+ breast cancer
Rituximab	CD20	B-cell lymphoma
Bevacizumab	VEGF (anti-angiogenesis)	Colorectal, lung, ovarian cancer
Cetuximab	EGFR	Colorectal, head & neck cancer

Kinase Inhibitors (end in -nib)

Drug	Target	Use
Imatinib (Gleevec)	BCR-ABL tyrosine kinase	CML (Philadelphia chromosome+)
Erlotinib	EGFR	Non-small cell lung cancer
Vemurafenib	BRAF V600E mutation	Melanoma

G. Immunotherapy (Checkpoint Inhibitors)

Mechanism: Block PD-1, PD-L1, or CTLA-4 to "unleash" the immune system against cancer.

Drug	Target	Use
Pembrolizumab (Keytruda)	PD-1	Melanoma, NSCLC, many others
Nivolumab (Opdivo)	PD-1	Melanoma, RCC, NSCLC
Atezolizumab	PD-L1	Bladder, NSCLC
Ipilimumab (Yervoy)	CTLA-4	Melanoma

Side effects: Immune-related adverse events (irAEs) - colitis, pneumonitis, hepatitis, endocrinopathies

4. Common Side Effects Summary

Side Effect	Drugs Responsible
Myelosuppression	Almost all chemo drugs
Nausea/Vomiting	Cisplatin (most emetogenic), cyclophosphamide
Alopecia	Doxorubicin, cyclophosphamide
Cardiomyopathy	Doxorubicin, daunorubicin
Pulmonary fibrosis	Bleomycin, busulfan
Hemorrhagic cystitis	Cyclophosphamide, ifosfamide → prevented by Mesna
Nephrotoxicity	Cisplatin → give IV fluids + amifostine
Peripheral neuropathy	Vincristine, paclitaxel, cisplatin
Ototoxicity	Cisplatin
Hand-foot syndrome	5-FU, capecitabine
Neurotoxicity (CNS)	High-dose cytarabine (cerebellar), ifosfamide

5. Cell Cycle Targets - Quick Visual

G1 (Growth)  →  S phase (DNA synthesis)  →  G2  →  M phase (Mitosis)
                      ↑                              ↑
              Antimetabolites                  Vinca alkaloids
              (Methotrexate, 5-FU)             Taxanes
                                               Etoposide

Alkylating agents, Antibiotics (Doxorubicin) → Cell Cycle NON-specific

6. Important Drug Interactions to Remember

Drug	Interaction	Effect
Methotrexate + NSAIDs	NSAIDs decrease MTX excretion	Increased MTX toxicity
6-MP + Allopurinol	Allopurinol inhibits xanthine oxidase (metabolizes 6-MP)	Increase 6-MP levels → reduce dose 50-75%
Cyclophosphamide	Enhanced toxicity with other immunosuppressants
Leucovorin	"Rescue" after high-dose MTX	Reverses folate depletion

7. Quick Mnemonics

"MOPP" - Classic Hodgkin lymphoma regimen: Mechlorethamine, Oncovin (vincristine), Procarbazine, Prednisone
"ABVD" - Modern Hodgkin regimen: Adriamycin (doxorubicin), Bleomycin, Vinblastine, Dacarbazine
"CMF" - Breast cancer: Cyclophosphamide, Methotrexate, 5-Fluorouracil
"Bleomycin = Breathe-o-mycin" → lung toxicity (pulmonary fibrosis)
"Cis-PLATin" → think PLATinum → nephrotoxic, give PLENTY of fluids

Source: Lippincott Illustrated Reviews: Pharmacology, Chapter 37 - Anticancer Drugs

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