Classification of Anti cancer drugs

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I now have all the information needed. Here is the comprehensive classification of anticancer drugs.

Classification of Anticancer Drugs

Anticancer drugs are classified along two main axes: (1) mechanism/pharmacological class and (2) cell cycle specificity. Both frameworks are used in practice and in exam settings.

Framework 1: Cell Cycle-Based Classification

This is fundamental to understanding scheduling and combination chemotherapy. Two major groups exist:

Source: Katzung's Basic and Clinical Pharmacology, 16th Edition (Table 54-1)

A. Cell Cycle-Specific (CCS) Agents

These drugs kill cells only when they are actively traversing the cell cycle. They are most effective against tumors with a high growth fraction.

Subclass	Phase	Key Drugs
Antimetabolites	S phase	Methotrexate (MTX), 5-Fluorouracil (5-FU), Capecitabine, Gemcitabine, Cytarabine (ara-C), 6-Mercaptopurine (6-MP), 6-Thioguanine, Fludarabine, Cladribine, Clofarabine, TAS-102
Topoisomerase II inhibitors	G1-S phase	Etoposide
Topoisomerase I inhibitors (Camptothecins)	G2-M phase	Irinotecan (CPT-11), Topotecan, Govitecan (SN-38), Deruxtecan (DXd)
Taxanes	M phase	Paclitaxel, Docetaxel, Cabazitaxel, Nab-paclitaxel
Vinca Alkaloids	M phase	Vincristine, Vinblastine, Vinorelbine
Antimicrotubule inhibitors	M phase	Ixabepilone, Eribulin
Antitumor antibiotics (some)	G2-M phase	Bleomycin

B. Cell Cycle-Nonspecific (CCNS) Agents

These drugs can kill both cycling AND resting (G0) cells - they work regardless of the cell cycle phase, though cycling cells are still more sensitive.

Subclass	Key Drugs
Alkylating agents	Cyclophosphamide, Chlorambucil, Mechlorethamine, Melphalan, Busulfan, Carmustine (BCNU), Lomustine (CCNU), Dacarbazine, Temozolomide, Thiotepa, Bendamustine, Altretamine, Trabectedin, Lurbinectedin
Antitumor antibiotics	Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Mitoxantrone (anthracyclines), Dactinomycin, Mitomycin C
Platinum analogs	Cisplatin, Carboplatin, Oxaliplatin

Framework 2: Pharmacological/Mechanistic Classification

1. Alkylating Agents

Form covalent bonds with DNA (especially N-7 of guanine), causing intrastrand and interstrand DNA crosslinks that block replication.

Subclasses:

Nitrogen mustards: Cyclophosphamide, Ifosfamide, Chlorambucil, Mechlorethamine, Melphalan
Nitrosoureas (lipid-soluble, cross BBB): Carmustine (BCNU), Lomustine (CCNU), Streptozocin
Alkyl sulfonates: Busulfan
Triazines/Imidazotetrazines: Dacarbazine, Temozolomide
Ethylenimine: Thiotepa, Altretamine
Others: Bendamustine, Trabectedin, Lurbinectedin

Key toxicity: Myelosuppression, mucosal damage, gonadal toxicity, secondary malignancies (especially AML); cyclophosphamide causes hemorrhagic cystitis (prevented by mesna).

2. Antimetabolites

Structurally similar to normal metabolites; interfere with DNA/RNA synthesis by competing with natural substrates or by fraudulent incorporation.

Subclasses:

Folate antagonists: Methotrexate, Pemetrexed - inhibit dihydrofolate reductase (DHFR); block thymidylate and purine synthesis
Pyrimidine analogs:
- 5-Fluorouracil (5-FU) - inhibits thymidylate synthase
- Capecitabine - oral prodrug of 5-FU
- Cytarabine (ara-C) - inhibits DNA polymerase (used in leukemia)
- Gemcitabine - inhibits ribonucleotide reductase and DNA polymerase
- TAS-102 (trifluridine/tipiracil)
Purine analogs:
- 6-Mercaptopurine (6-MP), 6-Thioguanine - inhibit de novo purine synthesis
- Fludarabine, Cladribine, Clofarabine - used in lymphoid malignancies

3. Natural Products

a) Vinca Alkaloids

Derived from the periwinkle plant (Vinca rosea). Inhibit tubulin polymerization → block mitotic spindle formation → arrest in M phase (metaphase).

Drugs: Vincristine, Vinblastine, Vinorelbine
Key toxicity: Vincristine - peripheral neuropathy (NOT myelosuppression); Vinblastine - myelosuppression

b) Taxanes

Stabilize microtubules (opposite to vincas) → prevent depolymerization → mitotic arrest.

Drugs: Paclitaxel (Taxol), Docetaxel, Cabazitaxel, Nab-paclitaxel
Key toxicity: Peripheral neuropathy, myelosuppression, hypersensitivity

c) Topoisomerase Inhibitors

Topo I inhibitors (Camptothecins): Irinotecan, Topotecan - cause single-strand DNA breaks; irinotecan converted to active SN-38 by carboxylesterase
Topo II inhibitors: Etoposide (epipodophyllotoxin) - prevents relegation of DNA strands → double-strand breaks

d) Antitumor Antibiotics

Products of Streptomyces species:

Anthracyclines: Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Mitoxantrone - intercalate DNA, inhibit topo II, generate free radicals. Key toxicity: cumulative dose-dependent cardiomyopathy (mechanism: free radical injury)
Bleomycin: Generates oxygen free radicals → single- and double-strand DNA breaks. Key toxicity: pulmonary fibrosis
Mitomycin C: Alkylates DNA after bioreductive activation
Dactinomycin (Actinomycin D): Intercalates between G-C base pairs, blocks RNA polymerase

4. Platinum Analogs

Coordinate covalently with DNA, forming intrastrand crosslinks (mainly between adjacent guanines) - functionally similar to alkylators but classified separately.

Cisplatin: Used in testicular, ovarian, bladder, lung, head and neck cancers. Key toxicity: nephrotoxicity (prevent with vigorous hydration), ototoxicity, peripheral neuropathy
Carboplatin: Less nephrotoxic/neurotoxic, more myelosuppressive than cisplatin
Oxaliplatin: Cold-induced peripheral neuropathy (unique); used in colorectal cancer (FOLFOX regimen)

5. Targeted Therapy

a) Monoclonal Antibodies (mAbs - suffix "-mab")

Drug	Target	Indication
Trastuzumab	HER2	Breast, gastric cancer
Rituximab	CD20	B-cell lymphoma, CLL
Bevacizumab	VEGF-A	CRC, NSCLC, ovarian, cervical, RCC
Cetuximab, Panitumumab	EGFR (HER1)	CRC, head and neck
Ramucirumab	VEGF-R2	Gastric, NSCLC, CRC, HCC
Ziv-aflibercept	VEGF-A, VEGF-B, PlGF (decoy receptor)	CRC

b) Small Molecule Tyrosine Kinase Inhibitors (TKIs - suffix "-ib")

BCR-ABL inhibitors: Imatinib, Dasatinib, Nilotinib (CML - Philadelphia chromosome positive)
EGFR inhibitors: Erlotinib, Gefitinib, Osimertinib (NSCLC)
HER2 inhibitors: Lapatinib, Neratinib
VEGFR inhibitors (multi-kinase): Sorafenib, Sunitinib, Pazopanib, Cabozantinib
ALK inhibitors: Crizotinib, Alectinib (ALK+ NSCLC)
BRAF inhibitors: Vemurafenib, Dabrafenib (BRAF V600E melanoma)
CDK4/6 inhibitors: Palbociclib, Ribociclib, Abemaciclib (breast cancer)
PARP inhibitors: Olaparib, Rucaparib (BRCA-mutated ovarian, breast cancer)
BTK inhibitors: Ibrutinib (CLL, mantle cell lymphoma)
mTOR inhibitors: Everolimus, Temsirolimus (RCC, breast cancer)
PI3K inhibitors: Idelalisib (CLL, follicular lymphoma)
JAK inhibitors: Ruxolitinib (myelofibrosis, polycythemia vera)

c) Antibody-Drug Conjugates (ADCs)

Monoclonal antibody linked to a cytotoxic payload:

Trastuzumab emtansine (T-DM1) - HER2+ breast cancer
Trastuzumab deruxtecan (T-DXd) - HER2+ breast, gastric cancer (Deruxtecan is a topo I inhibitor)
Brentuximab vedotin - CD30+ lymphoma

6. Hormonal Agents

Used in hormone-sensitive tumors (breast, prostate, endometrial).

Subclass	Drugs	Use
Selective Estrogen Receptor Modulators (SERMs)	Tamoxifen	ER+ breast cancer
Aromatase inhibitors	Anastrozole, Letrozole, Exemestane	Postmenopausal ER+ breast cancer
GnRH analogs	Leuprolide, Goserelin	Prostate cancer (medical castration)
Antiandrogens	Enzalutamide, Flutamide, Bicalutamide	Prostate cancer
Progestins	Megestrol acetate	Endometrial, breast
Estrogens (supraphysiologic)	Diethylstilbestrol	Prostate cancer

7. Immunotherapy / Immune Checkpoint Inhibitors

Unleash the immune system against cancer by blocking inhibitory checkpoints.

Drug	Target	Indications
Ipilimumab	CTLA-4	Melanoma
Pembrolizumab, Nivolumab	PD-1	Melanoma, NSCLC, bladder, many others
Atezolizumab, Durvalumab	PD-L1	NSCLC, bladder, triple-negative breast

8. Miscellaneous Agents

Hydroxyurea: Inhibits ribonucleotide reductase (S phase specific); used in CML, sickle cell disease
L-Asparaginase: Depletes asparagine (ALL cells cannot synthesize asparagine); used in ALL
Arsenic trioxide: Induces differentiation/apoptosis in APL (acute promyelocytic leukemia)
All-trans retinoic acid (ATRA): Differentiating agent in APL
Proteasome inhibitors: Bortezomib, Carfilzomib (multiple myeloma)
Thalidomide/Lenalidomide/Pomalidomide (IMiDs): Anti-angiogenic + immunomodulatory; multiple myeloma
Venetoclax: BCL-2 inhibitor; CLL, AML

Quick Memory Summary

Class	Prototype	Key Mechanism
Alkylating agent	Cyclophosphamide	DNA crosslinks
Antimetabolite	Methotrexate	Inhibit DHFR
Vinca alkaloid	Vincristine	Tubulin depolymerization
Taxane	Paclitaxel	Tubulin stabilization
Anthracycline	Doxorubicin	Topo II + free radicals
Platinum analog	Cisplatin	Intrastrand DNA crosslinks
Topo I inhibitor	Irinotecan	DNA single-strand breaks
Topo II inhibitor	Etoposide	DNA double-strand breaks
Hormonal	Tamoxifen	ER antagonism
Targeted	Imatinib	BCR-ABL TK inhibition
Checkpoint inhibitor	Pembrolizumab	Anti-PD-1

Sources: Katzung's Basic and Clinical Pharmacology, 16th Edition (Chapter 54 - Cancer Chemotherapy); Goldman-Cecil Medicine, International Edition

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