Anti cancer drugs pharma bds 2 nd year

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Anti-Cancer Drugs (Antineoplastic Agents)

BDS 2nd Year Pharmacology Source: Katzung's Basic and Clinical Pharmacology, 16th Ed.

1. Introduction

Cancer is a disease of uncontrolled cell proliferation characterized by loss of normal growth regulation, genetic instability, and capacity for metastasis. In 2023, approximately 1.9 million new cancer cases were diagnosed in the USA alone, with ~609,000 deaths. A small subpopulation of tumor stem cells retain clonogenic (colony-forming) ability and drive resistance to therapy.

Treatment modalities: Surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy. Chemotherapy is used as:

Primary induction - for advanced/metastatic disease
Neoadjuvant - before surgery/radiation to shrink the tumor
Adjuvant - after surgery to eliminate micrometastases

2. Cell Cycle Kinetics - The Foundation

Understanding cell cycle phases is critical to anti-cancer drug action:

Phase	Event
G1	Growth, protein synthesis
S	DNA synthesis (replication)
G2	Pre-mitotic gap
M	Mitosis (cell division)
G0	Resting/quiescent phase

Two Major Drug Classes Based on Cell Cycle:

Class	Description	Examples
Cell Cycle-Specific (CCS)	Kill only cycling cells, active in specific phase	Antimetabolites (S phase), Vinca alkaloids & Taxanes (M phase)
Cell Cycle-Nonspecific (CCNS)	Kill both cycling and resting G0 cells	Alkylating agents, Antitumor antibiotics, Platinum analogs, Anthracyclines

3. Classification of Anti-Cancer Drugs

I. ALKYLATING AGENTS (CCNS)

Mechanism: Form covalent bonds with DNA - alkylate the N-7 position of guanine, causing cross-linking of DNA strands, abnormal base pairing, and strand breaks. This prevents DNA replication and transcription.

Subgroups:

A. Nitrogen Mustards

Cyclophosphamide - most widely used; requires hepatic activation to active metabolites (acrolein + phosphoramide mustard). Used in breast cancer, lymphomas, leukemias. Toxicity: hemorrhagic cystitis (prevented by mesna), myelosuppression, alopecia, SIADH
Mechlorethamine - prototype; used in Hodgkin lymphoma (MOPP regimen)
Melphalan - used in multiple myeloma
Chlorambucil - used in CLL (chronic lymphocytic leukemia)

B. Nitrosoureas (cross blood-brain barrier)

Carmustine (BCNU) and Lomustine (CCNU) - used in brain tumors (gliomas) and Hodgkin lymphoma. Highly lipid-soluble; cross BBB. Toxicity: delayed and cumulative myelosuppression

C. Alkyl Sulfonates

Busulfan - used in CML and pre-bone marrow transplant conditioning. Toxicity: pulmonary fibrosis, skin hyperpigmentation, busulfan lung

D. Triazenes

Dacarbazine (DTIC) - used in melanoma, Hodgkin lymphoma (ABVD regimen)
Temozolomide - oral; used in glioblastoma multiforme. Crosses BBB.

E. Thiotepa - used in bladder cancer (intravesical instillation)

II. PLATINUM ANALOGS (CCNS)

Mechanism: Similar to alkylating agents - form platinum-DNA adducts (intra- and inter-strand cross-links), inhibiting DNA replication.

Drug	Key Uses	Key Toxicity
Cisplatin	Testicular, ovarian, bladder, lung, head & neck cancers	Severe nephrotoxicity (requires aggressive hydration), ototoxicity (irreversible hearing loss), nausea/vomiting (worst emetogen), peripheral neuropathy
Carboplatin	Ovarian, lung cancers	Myelosuppression (dose-limiting); less nephrotoxic/neurotoxic than cisplatin
Oxaliplatin	Colorectal cancer (FOLFOX regimen with 5-FU + leucovorin)	Peripheral sensory neuropathy (dose-limiting), cold-induced dysesthesias

III. ANTIMETABOLITES (CCS - S Phase)

Mechanism: Structural analogs of normal cellular metabolites; interfere with nucleotide synthesis or DNA synthesis during S phase.

A. Folate Antagonists

Methotrexate (MTX): Inhibits dihydrofolate reductase (DHFR) → blocks conversion of dihydrofolate to tetrahydrofolate (THF) → depletes folate pool → inhibits purine synthesis and thymidylate synthesis. Used in ALL, breast cancer, choriocarcinoma, osteosarcoma, lymphomas, RA, psoriasis. Toxicity: mucositis, myelosuppression, hepatotoxicity, nephrotoxicity. Rescue with leucovorin (folinic acid).

B. Pyrimidine Analogs

5-Fluorouracil (5-FU): Inhibits thymidylate synthase → blocks dTMP synthesis → "thymineless death." Also incorporated into RNA. Used in colorectal, breast, head & neck, gastric cancers. Given with leucovorin to enhance activity. Toxicity: mucositis, diarrhea, myelosuppression, hand-foot syndrome (palmar-plantar erythrodysesthesia). Increased toxicity in DPD (dihydropyrimidine dehydrogenase) deficiency.
Capecitabine: Oral prodrug of 5-FU; converted to 5-FU preferentially in tumor tissue. Used in colorectal and breast cancers.
Cytarabine (Ara-C): Incorporated into DNA, inhibits DNA polymerase. Major drug for AML (acute myelogenous leukemia). Toxicity: severe myelosuppression, cerebellar toxicity (high dose), "Ara-C syndrome."
Gemcitabine: Inhibits ribonucleotide reductase and DNA polymerase. Used in pancreatic, NSCLC, bladder, ovarian cancers. Toxicity: myelosuppression, flu-like syndrome.

C. Purine Analogs

6-Mercaptopurine (6-MP): Inhibits purine de novo synthesis. Used in ALL maintenance therapy. Metabolized by xanthine oxidase - dose must be reduced by 75% when used with allopurinol.
6-Thioguanine: Similar to 6-MP; used in AML.
Fludarabine: Purine analog for CLL and low-grade lymphomas. Immunosuppressive (reduces CD4/CD8 T cells).
Cladribine: High specificity for lymphoid cells; used in hairy cell leukemia.

IV. ANTITUMOR ANTIBIOTICS (CCNS)

A. Anthracyclines

Mechanism: Intercalation into DNA, inhibition of topoisomerase II, generation of free radicals causing DNA strand breaks
Doxorubicin (Adriamycin): Broadest spectrum - breast, lymphomas, sarcomas, leukemias. Toxicity: cardiomyopathy (dose-dependent, cumulative; limit total dose <550 mg/m²), myelosuppression, alopecia, mucositis, red urine (not hematuria). Potent vesicant.
Daunorubicin: AML, ALL. Also cardiotoxic.
Idarubicin: AML.
Epirubicin: Breast cancer.
Mitoxantrone: AML, prostate cancer, multiple sclerosis (less cardiotoxic than doxorubicin).

B. Other Antitumor Antibiotics

Bleomycin: Generates oxygen free radicals that cause single- and double-strand DNA breaks. Used in Hodgkin lymphoma (ABVD regimen), testicular cancer, head & neck cancer. Toxicity: pulmonary fibrosis (dose-limiting), skin toxicity, mucositis. Minimal myelosuppression. Hyperoxia increases lung toxicity (caution intraoperatively).
Dactinomycin (Actinomycin D): Intercalates into DNA; inhibits RNA synthesis. Used in Wilms tumor, rhabdomyosarcoma, choriocarcinoma.
Mitomycin C: Activated to an alkylating agent; used in bladder cancer (intravesical), gastric cancer.

V. NATURAL PRODUCTS

A. Vinca Alkaloids (CCS - M Phase)

Mechanism: Inhibit tubulin polymerization → disrupt microtubule assembly → mitotic arrest in metaphase → cell death. Active in M phase.

Drug	Source	Key Uses	Dose-Limiting Toxicity
Vincristine	Vinca rosea (periwinkle)	ALL, Hodgkin & non-Hodgkin lymphoma, Wilms tumor, neuroblastoma, rhabdomyosarcoma	Peripheral neuropathy (sensory + autonomic - constipation/ileus, SIADH); minimal myelosuppression
Vinblastine	Vinca rosea	Hodgkin lymphoma, testicular, breast cancer	Myelosuppression (bone marrow suppression); nausea/vomiting
Vinorelbine	Semisynthetic	NSCLC, breast cancer	Neutropenia (myelosuppression)

Memory tip: Vincristine = Cranial/peripheral nerve toxicity; Vinblastine = Bone marrow suppression

All vinca alkaloids are potent vesicants and are metabolized by liver CYP450 (dose reduction needed in liver dysfunction).

B. Taxanes (CCS - M Phase)

Mechanism: Opposite to vinca alkaloids - promote tubulin polymerization (stabilize microtubules) → prevent depolymerization → mitotic arrest → cell death.
Paclitaxel: Derived from Pacific yew (Taxus brevifolia). Used in ovarian, breast, NSCLC, SCLC, head & neck, prostate, bladder cancers. Toxicity: myelosuppression, peripheral neuropathy, hypersensitivity reactions (HSR; prevented by premedication with dexamethasone + diphenhydramine + H2-blocker), alopecia.
Docetaxel: Similar to paclitaxel; fluid retention syndrome is notable toxicity.
Nab-paclitaxel (albumin-bound): No HSR risk; approved for breast, pancreatic, NSCLC.

C. Topoisomerase Inhibitors

Etoposide (VP-16): Inhibits topoisomerase II → DNA strand breaks. Used in testicular cancer, SCLC, lymphomas. Toxicity: myelosuppression, alopecia, secondary leukemia.
Irinotecan: Inhibits topoisomerase I. Used in colorectal cancer (FOLFIRI regimen). Toxicity: severe diarrhea (early - cholinergic; late - treat with loperamide), myelosuppression.
Topotecan: Inhibits topoisomerase I. Used in ovarian cancer, SCLC.

VI. HORMONAL AGENTS

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

Drug	Class	Mechanism	Use
Tamoxifen	SERM	Competitive antagonist at estrogen receptors in breast tissue	ER+/PR+ breast cancer (adjuvant); may increase endometrial cancer risk
Aromatase inhibitors (anastrozole, letrozole, exemestane)	AIs	Block peripheral conversion of androgens to estrogens	Post-menopausal ER+ breast cancer
Leuprolide, Goserelin	GnRH agonists	Suppress LH/FSH → reduce testosterone	Prostate cancer
Flutamide, Bicalutamide	Antiandrogens	Block androgen receptor	Prostate cancer
Megestrol acetate	Progestogen	Feedback suppression of gonadotropins	Endometrial, breast cancers

VII. TARGETED THERAPY / MOLECULAR-TARGETED AGENTS

A. Tyrosine Kinase Inhibitors (TKIs)

BCR-ABL Inhibitors (for CML - Philadelphia chromosome t(9;22)):

Imatinib (Gleevec): First-generation; also inhibits PDGFR and c-kit (used in GIST). First-line CML.
Dasatinib, Nilotinib: Second-generation; overcome most imatinib-resistant mutations.
Ponatinib: Third-generation; active against T315I ("gatekeeper") mutation.
All metabolized by CYP3A4; avoid grapefruit products.

EGFR Inhibitors:

Erlotinib, Gefitinib: NSCLC with EGFR mutations.
Cetuximab: EGFR antibody; colorectal cancer, head & neck cancer.

HER2 Inhibitors:

Lapatinib: HER2+ breast cancer (combined with capecitabine).

VEGFR/Anti-angiogenic:

Sorafenib, Sunitinib: Multi-kinase inhibitors; renal cell carcinoma, HCC, GIST.
Bevacizumab: Anti-VEGF monoclonal antibody; colorectal, NSCLC, ovarian, glioblastoma.

BRAF Inhibitors:

Vemurafenib, Dabrafenib: BRAF V600E mutation-positive melanoma.

VIII. IMMUNOTHERAPY

Checkpoint Inhibitors:
- Anti-PD-1: Pembrolizumab, Nivolumab - used in melanoma, NSCLC, many solid tumors
- Anti-CTLA-4: Ipilimumab - melanoma
- Anti-PD-L1: Atezolizumab, Durvalumab
Rituximab: Anti-CD20 monoclonal antibody; B-cell NHL, CLL.
Trastuzumab (Herceptin): Anti-HER2 antibody; HER2+ breast and gastric cancer.

4. General Adverse Effects of Chemotherapy

System	Effect
Bone marrow	Myelosuppression - neutropenia (infection risk), thrombocytopenia (bleeding), anemia
GI tract	Nausea, vomiting, mucositis, diarrhea
Hair follicles	Alopecia (reversible)
Gonads	Infertility, teratogenicity
Bladder	Hemorrhagic cystitis (cyclophosphamide/ifosfamide - prevented by mesna)
Lung	Pulmonary fibrosis (bleomycin, busulfan, carmustine)
Heart	Cardiomyopathy (doxorubicin, daunorubicin)
Kidney	Nephrotoxicity (cisplatin, methotrexate)
Nerves	Peripheral neuropathy (vincristine, cisplatin, paclitaxel)
Secondary malignancy	Especially secondary leukemia (alkylating agents, etoposide)

5. Principles of Combination Chemotherapy

Drugs are combined to:

Maximize cell kill within tolerable toxicity
Overcome drug resistance (different mechanisms)
Target different phases of cell cycle
Broaden spectrum of activity

Rules:

Use drugs with different mechanisms of action
Use drugs with non-overlapping toxicities
Use drugs individually active against the cancer

Important regimens to know:

Regimen	Drugs	Cancer
ABVD	Doxorubicin (Adriamycin), Bleomycin, Vinblastine, Dacarbazine	Hodgkin lymphoma (1st line)
CHOP	Cyclophosphamide, Doxorubicin (Adriamycin/hydroxydaunorubicin), Vincristine (Oncovin), Prednisone	Non-Hodgkin lymphoma
FOLFOX	5-FU, Leucovorin, Oxaliplatin	Colorectal cancer
BEP	Bleomycin, Etoposide, Cisplatin (Platinum)	Testicular cancer
CMF	Cyclophosphamide, Methotrexate, 5-FU	Breast cancer

6. Quick-Review Summary Table

Class	Mechanism	Key Drugs	Key Toxicity
Alkylating agents	DNA cross-linking	Cyclophosphamide, Cisplatin, Busulfan	Myelosuppression, hemorrhagic cystitis, pulmonary fibrosis
Antimetabolites	Block nucleotide/DNA synthesis	Methotrexate, 5-FU, Cytarabine	Mucositis, myelosuppression
Antitumor antibiotics	Intercalation, topo II inhibition, free radicals	Doxorubicin, Bleomycin, Dactinomycin	Cardiotoxicity (dox), pulmonary fibrosis (bleo)
Vinca alkaloids	Inhibit tubulin polymerization (M phase)	Vincristine, Vinblastine	Neuropathy (VCR), myelosuppression (VBL)
Taxanes	Stabilize microtubules (M phase)	Paclitaxel, Docetaxel	Myelosuppression, neuropathy, HSR
Topo inhibitors	Inhibit topo I or II	Etoposide, Irinotecan	Myelosuppression, diarrhea
Hormonal	Block hormone receptor or synthesis	Tamoxifen, AIs, Leuprolide	Depends on drug
Targeted therapy	Block specific kinases/receptors	Imatinib, Trastuzumab, Bevacizumab	Variable; QTc prolongation, rash

Reference: Katzung's Basic and Clinical Pharmacology, 16th Ed., Chapter 54: Cancer Chemotherapy; Goodman & Gilman's Pharmacological Basis of Therapeutics.

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