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🧠 MASTER LOGIC: “Where does the drug attack the cancer cell?”
Cancer cells differ from normal cells mainly by:
- Rapid DNA synthesis
- Faulty DNA repair
- High mitotic activity
👉 So chemotherapy targets DNA synthesis, DNA structure, or mitosis
Everything else (uses, side effects, regimens) follows from this.
1️⃣ Drugs that BLOCK DNA BUILDING
(S-phase specific → affect fastest dividing tissues)
🔹 Antimetabolites = “Fake building blocks”
🔸 Methotrexate (MTX) — blocks folate → no thymidine
Logic
- DNA needs thymidine
- Thymidine needs tetrahydrofolate
- MTX blocks DHFR
➡️ DNA synthesis stops → S-phase arrest
Why trophoblastic disease responds
- Trophoblast = extremely rapid DNA synthesis
- So MTX alone is enough in low-risk GTN
Classic toxicities (predictable from logic)
- Bone marrow suppression (fast dividing)
- Mucositis (oral epithelium)
- GI upset, hepatotoxicity
Rescue
- Folinic acid (leucovorin) bypasses DHFR block
🔸 5-Fluorouracil (5-FU) — blocks thymidine directly
Logic
- Thymidine synthase makes thymidine
- 5-FU inhibits it
➡️ No thymidine → DNA failure
Why used with radiotherapy
- Radiation damages DNA
- 5-FU prevents repair
➡️ Radiosensitiser
Toxicities
- Mucositis
- Diarrhoea
- Hand–foot syndrome
- Myelosuppression
2️⃣ Drugs that DAMAGE DNA STRUCTURE
(Cell-cycle non-specific but kill dividing cells best)
🔹 Alkylating agents & platinum compounds
= “Tie DNA strands together”
🔸 Cyclophosphamide / Ifosfamide
Logic
- Add alkyl groups → DNA crosslinks
- DNA can’t unwind → replication fails
Why haemorrhagic cystitis
- Acrolein metabolite concentrates in bladder
- Hence mesna + hydration
Why infertility & second cancers
- Non-selective DNA damage to germ cells
🔸 Platinum drugs (Cisplatin, Carboplatin)
Logic
- Heavy metals bind DNA
- Cause intra- & inter-strand crosslinks
- Trigger apoptosis
Cisplatin vs Carboplatin (pure logic)
Feature | Cisplatin | Carboplatin |
DNA binding | Strong | Slightly weaker |
Kidney | Nephrotoxic | Safer |
Ear | Ototoxic | Minimal |
Bone marrow | Moderate | More myelosuppression |
Use | Radiosensitiser | Long-term chemo |
💡 Why ovarian cancer is platinum-sensitive
- High DNA repair defects
- Platinum damage overwhelms repair
➡️ Excellent response rates
Exam rule
- Relapse > 6 months → platinum-sensitive
- Use carboplatin again
3️⃣ Drugs that BREAK DNA STRANDS
🔹 Anti-tumour antibiotics / Topoisomerase inhibitors
🔸 Doxorubicin
Triple attack
- DNA intercalation
- Topoisomerase II inhibition
- Free radical generation
Why cardiomyopathy
- Heart has poor antioxidant defences
- Damage is dose-dependent & irreversible
🔸 Etoposide
Logic
- Blocks topoisomerase II
- DNA breaks accumulate
- Apoptosis triggered
Why secondary leukaemia
- Chronic DNA strand damage in marrow stem cells
🔸 Bleomycin
Logic
- Free radical DNA damage
- G2 phase effect
Why lung fibrosis
- Lungs lack bleomycin-inactivating enzyme
4️⃣ Drugs that STOP MITOSIS
(M-phase specific)
🔹 Microtubule inhibitors = “Freeze the spindle”
🔸 Vincristine (Vinca alkaloid)
Logic
- Prevents microtubule assembly
- Spindle can’t form
- Cell stuck in metaphase
Why neuropathy
- Axonal transport depends on microtubules
🔸 Paclitaxel (Taxane)
Opposite mechanism
- Over-stabilises microtubules
- Can’t disassemble
➡️ Same result: metaphase arrest
Why alopecia
- Hair follicles = rapid mitosis
5️⃣ REGIMEN LOGIC (This is what examiners love)
🟣 OVARIAN CANCER
Problem: DNA repair defect
Solution: DNA damage + mitotic block
➡️ Carboplatin + Paclitaxel
🟡 ENDOMETRIAL CANCER
Less chemosensitive
- Use when recurrent / metastatic
Options:
- Carboplatin + Paclitaxel
- Doxorubicin + Cisplatin
🔴 CERVICAL CANCER
Key principle: Radiosensitisation
➡️ Cisplatin + Radiotherapy
- Cisplatin prevents DNA repair after radiation
🟠 VULVAL CANCER
Often elderly / unfit for surgery
➡️ 5-FU ± Cisplatin + RT
- Local control
- Symptom palliation
🟢 TROPHOBLASTIC DISEASE (GTN)
Core logic
- Fastest dividing tumour in medicine
- Highly chemosensitive
Low risk
➡️ Methotrexate alone
High risk
➡️ EMA-CO
- Multi-pathway attack
- Prevents resistance
- Cure ≈ 99%
6️⃣ SIDE-EFFECTS — ALL FROM ONE PRINCIPLE
Chemo kills fast-dividing normal cells
📉 Bone marrow
- Neutropenia (day 7–14 nadir)
- Anaemia
- Thrombocytopenia
🍽 GI tract
- Mucositis
- Diarrhoea
- Nausea/vomiting (cisplatin worst)
💇 Hair follicles
- Alopecia (taxanes, doxorubicin)
🧠 Nerves
- Vincristine → neuropathy
- Cisplatin → neuropathy + ototoxicity
❤️ Organ-specific
- Doxorubicin → cardiomyopathy
- Cisplatin → kidney + ear
- Bleomycin → lungs
🧩 ONE-LINE EXAM MEMORY MAP
- DNA synthesis blocked → MTX, 5-FU → mucositis, marrow
- DNA crosslinked → Cyclophosphamide, Platinum → marrow, organs
- DNA broken → Doxorubicin, Etoposide → heart, leukaemia
- Mitosis blocked → Vincristine, Paclitaxel → neuropathy, alopecia
🧠 MASTER CHEMOTHERAPY LOGIC TABLE
“Where does the drug attack the cancer cell?”
TARGET LEVEL | DRUG CLASS | KEY DRUGS | CELL-CYCLE PHASE | CORE MECHANISM (LOGIC) | WHY IT WORKS (HIGH-YIELD LOGIC) | SIGNATURE TOXICITIES (LOGIC-DERIVED) | CLASSIC EXAM USES / NOTES |
DNA BUILDING (S-phase) | Antimetabolites | Methotrexate (MTX) | S-phase specific | Inhibits DHFR → ↓ tetrahydrofolate → ↓ thymidine → DNA synthesis stops | Tumors with extreme DNA synthesis collapse quickly | Bone marrow suppression, mucositis, GI upset, hepatotoxicity | Low-risk GTN, leukemia, lymphoma; Leucovorin rescue |
5-Fluorouracil (5-FU) | S-phase specific | Inhibits thymidylate synthase → no thymidine | Blocks DNA repair after radiation | Mucositis, diarrhoea, hand–foot syndrome, myelosuppression | Radiosensitiser (cervix, vulva, GI cancers) | ||
DNA STRUCTURE (Cross-linking) | Alkylating agents | Cyclophosphamide / Ifosfamide | Cell-cycle non-specific | Alkylates DNA → inter-strand crosslinks → replication failure | Non-selective DNA damage kills dividing cells best | Myelosuppression, infertility, haemorrhagic cystitis | Breast, lymphoma; Mesna + hydration |
Platinum compounds | Cisplatin | Cell-cycle non-specific | Platinum binds DNA → intra/inter-strand crosslinks → apoptosis | Overwhelms defective DNA repair | Nephrotoxicity, ototoxicity, neuropathy, nausea/vomiting | Radiosensitiser, cervical cancer | |
Carboplatin | Cell-cycle non-specific | Same as cisplatin but weaker binding | Better tolerated for long-term use | Myelosuppression (more than cisplatin) | Ovarian cancer backbone | ||
DNA STRAND BREAKAGE | Anti-tumour antibiotics | Doxorubicin | Cell-cycle non-specific | DNA intercalation + Topo II inhibition + free radicals | Triple attack overwhelms tumour DNA | Cardiomyopathy (dose-dependent, irreversible) | Breast, sarcomas, gynae regimens |
Topoisomerase inhibitors | Etoposide | S–G₂ | Inhibits Topo II → double-strand breaks | Accumulated breaks → apoptosis | Secondary leukemia, myelosuppression | Germ cell tumours, lung | |
Free radical generators | Bleomycin | G₂ phase | Free-radical DNA damage | Lungs lack inactivating enzyme | Pulmonary fibrosis, minimal marrow toxicity | Testicular cancer | |
MITOSIS (M-phase) | Microtubule inhibitors | Vincristine | M-phase specific | Prevents microtubule assembly → metaphase arrest | No spindle → no division | Peripheral neuropathy, ileus | Leukemias, lymphomas |
Paclitaxel (Taxane) | M-phase specific | Over-stabilises microtubules → can’t disassemble | Spindle frozen | Alopecia, neuropathy, myelosuppression | Ovarian, endometrial cancer |
🎯 REGIMEN LOGIC (EXAM GOLD)
CANCER | BIOLOGIC PROBLEM | LOGIC-BASED REGIMEN | WHY IT WORKS |
Ovarian | DNA repair defect | Carboplatin + Paclitaxel | DNA damage + mitotic arrest |
Endometrial | Less chemosensitive | Carboplatin + Paclitaxel OR Doxorubicin + Cisplatin | Multi-pathway attack |
Cervical | Radiation-responsive | Cisplatin + RT | Prevents DNA repair (radiosensitisation) |
Vulval | Local control needed | 5-FU ± Cisplatin + RT | DNA synthesis block + radiosensitisation |
GTN (Low risk) | Fastest dividing tumour | Methotrexate alone | Extreme S-phase kill |
GTN (High risk) | Resistance risk | EMA-CO | Multi-mechanism, cure ≈ 99% |
🧩 ONE-LINE EXAM MEMORY LOCK (FROM TABLE)
- DNA synthesis blocked → MTX, 5-FU → mucositis, marrow
- DNA cross-linked → Cyclophosphamide, Platinum → marrow + organs
- DNA broken → Doxorubicin, Etoposide → heart, leukaemia
- Mitosis blocked → Vincristine, Paclitaxel → neuropathy, alopecia