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Tuesday, August 19, 2025

Antineoplastics


Introduction

Antineoplastics (also called anticancer agents, chemotherapy drugs, or cytotoxic agents) are a diverse group of pharmacological agents designed to inhibit the growth and spread of malignant cells. They achieve this through different mechanisms: interfering with cell division, DNA replication, metabolic pathways, or by modulating the immune system to target cancer cells.

These drugs are used in the treatment of a wide variety of cancers—solid tumors (e.g., breast, lung, colon, prostate cancers) and hematologic malignancies (e.g., leukemias, lymphomas, multiple myeloma). They may be used curatively, palliatively, or as adjuvant/neoadjuvant therapy alongside surgery and radiation.

Classification of Antineoplastic Agents

1. Alkylating Agents

  • Nitrogen mustards: Cyclophosphamide, Ifosfamide, Mechlorethamine, Melphalan, Chlorambucil

  • Nitrosoureas: Carmustine (BCNU), Lomustine (CCNU)

  • Alkyl sulfonates: Busulfan

  • Triazenes: Dacarbazine, Temozolomide

  • Platinum analogs: Cisplatin, Carboplatin, Oxaliplatin

2. Antimetabolites

  • Folate analogues: Methotrexate, Pemetrexed, Pralatrexate

  • Pyrimidine analogues: 5-Fluorouracil (5-FU), Capecitabine, Cytarabine, Gemcitabine

  • Purine analogues: 6-Mercaptopurine, 6-Thioguanine, Fludarabine, Cladribine

3. Natural Products

a) Vinca Alkaloids

  • Vincristine

  • Vinblastine

  • Vinorelbine

b) Taxanes

  • Paclitaxel

  • Docetaxel

  • Cabazitaxel

c) Epipodophyllotoxins

  • Etoposide

  • Teniposide

d) Camptothecins

  • Irinotecan

  • Topotecan

e) Anthracyclines (antitumor antibiotics)

  • Doxorubicin

  • Daunorubicin

  • Epirubicin

  • Idarubicin

f) Other antitumor antibiotics

  • Bleomycin

  • Mitomycin C

  • Dactinomycin

4. Hormonal Agents and Antagonists

a) Estrogen receptor modulators/antagonists

  • Tamoxifen, Toremifene, Fulvestrant

b) Aromatase inhibitors

  • Anastrozole, Letrozole, Exemestane

c) Androgen deprivation therapy

  • Flutamide, Bicalutamide, Enzalutamide, Apalutamide

  • Abiraterone (androgen biosynthesis inhibitor)

d) Corticosteroids

  • Prednisone, Dexamethasone (used in leukemias, lymphomas, supportive care)

e) Gonadotropin-releasing hormone (GnRH) analogues

  • Leuprolide, Goserelin, Triptorelin

5. Targeted Therapy

a) Tyrosine kinase inhibitors (TKIs)

  • Imatinib, Dasatinib, Nilotinib, Bosutinib (BCR-ABL inhibitors)

  • Erlotinib, Gefitinib, Osimertinib (EGFR inhibitors)

  • Sorafenib, Sunitinib, Pazopanib (multi-kinase inhibitors)

b) Monoclonal antibodies

  • Rituximab (anti-CD20)

  • Trastuzumab (anti-HER2)

  • Bevacizumab (anti-VEGF)

  • Cetuximab (anti-EGFR)

  • Daratumumab (anti-CD38)

c) Proteasome inhibitors

  • Bortezomib, Carfilzomib, Ixazomib

d) mTOR inhibitors

  • Everolimus, Temsirolimus

e) PARP inhibitors

  • Olaparib, Rucaparib, Niraparib

6. Immunotherapy (Immune Checkpoint Inhibitors)

  • CTLA-4 inhibitor: Ipilimumab

  • PD-1 inhibitors: Nivolumab, Pembrolizumab, Cemiplimab

  • PD-L1 inhibitors: Atezolizumab, Durvalumab, Avelumab

7. Miscellaneous Agents

  • Hydroxyurea

  • L-asparaginase

  • Arsenic trioxide

  • Mitotane

Mechanisms of Action

  • Alkylating agents: Covalently bind DNA → cross-linking → impaired replication and transcription → apoptosis.

  • Antimetabolites: Mimic natural nucleotides → inhibit DNA/RNA synthesis.

  • Vinca alkaloids and taxanes: Disrupt microtubule dynamics → inhibit mitosis.

  • Epipodophyllotoxins and camptothecins: Inhibit topoisomerases → DNA strand breaks.

  • Anthracyclines: Intercalate into DNA, inhibit topoisomerase II, generate free radicals.

  • Hormonal agents: Block or modulate hormone receptors (estrogen, androgen, progesterone).

  • Targeted therapies: Inhibit oncogenic proteins (tyrosine kinases, growth factor receptors, angiogenesis mediators).

  • Immunotherapies: Block immune checkpoints (PD-1, PD-L1, CTLA-4), restoring T-cell activity against cancer.

Clinical Uses

  • Leukemias & lymphomas: Methotrexate, cytarabine, cyclophosphamide, doxorubicin, rituximab.

  • Breast cancer: Tamoxifen, aromatase inhibitors, trastuzumab, paclitaxel.

  • Lung cancer: Cisplatin, etoposide, pemetrexed, EGFR inhibitors, PD-1 inhibitors.

  • Colorectal cancer: 5-FU, oxaliplatin, irinotecan, bevacizumab.

  • Prostate cancer: Androgen receptor antagonists, abiraterone, leuprolide.

  • Ovarian cancer: Carboplatin, paclitaxel, PARP inhibitors.

  • Multiple myeloma: Bortezomib, lenalidomide, daratumumab.

  • Melanoma: Ipilimumab, nivolumab, BRAF inhibitors (vemurafenib).

  • Pediatric cancers: Vincristine, asparaginase, methotrexate.

Dosage Examples (Selected)

  • Cyclophosphamide: 500–1000 mg/m² IV every 3 weeks or oral regimens.

  • Methotrexate: Low doses (7.5–25 mg/week for maintenance) or high-dose protocols (1–12 g/m² IV with leucovorin rescue).

  • 5-Fluorouracil (5-FU): 400–600 mg/m² IV bolus daily for 5 days.

  • Cisplatin: 50–100 mg/m² IV every 3–4 weeks.

  • Doxorubicin: 60–75 mg/m² IV every 3 weeks.

  • Imatinib: 400 mg orally once daily.

  • Pembrolizumab: 200 mg IV every 3 weeks or 400 mg every 6 weeks.

Doses vary widely depending on cancer type, patient factors, and treatment protocols.

Contraindications

  • Absolute:

    • Severe hypersensitivity to drug.

    • Profound bone marrow suppression.

    • Pregnancy (most antineoplastics are teratogenic).

  • Relative:

    • Renal or hepatic impairment.

    • Pre-existing cardiac disease (e.g., anthracyclines contraindicated in cardiomyopathy).

    • Poor performance status (frailty, ECOG ≥3).

Adverse Effects

General Chemotherapy Toxicities (common to many agents)

  • Myelosuppression: Neutropenia, anemia, thrombocytopenia.

  • Gastrointestinal: Nausea, vomiting, mucositis, diarrhea.

  • Alopecia.

  • Fatigue.

  • Infections (due to immunosuppression).

Drug-Specific Toxicities

  • Cyclophosphamide/Ifosfamide: Hemorrhagic cystitis (due to acrolein metabolite).

  • Cisplatin: Nephrotoxicity, ototoxicity, neurotoxicity.

  • Methotrexate: Hepatotoxicity, pulmonary fibrosis, mucositis.

  • 5-FU/Capecitabine: Hand-foot syndrome, cardiotoxicity.

  • Doxorubicin: Cumulative dose-related cardiomyopathy.

  • Bleomycin: Pulmonary fibrosis.

  • Vincristine: Peripheral neuropathy.

  • Taxanes: Hypersensitivity reactions, myelosuppression, neuropathy.

  • Checkpoint inhibitors: Immune-related adverse events (colitis, pneumonitis, endocrinopathies).

Precautions

  • Monitor CBC, renal and hepatic function before and during therapy.

  • Use growth factor support (G-CSF) for high-risk neutropenia.

  • Hydration and mesna (for cyclophosphamide/ifosfamide) to prevent cystitis.

  • Cardiac monitoring with anthracyclines.

  • Strict contraception during and after therapy due to teratogenicity.

  • Vaccination and infection prophylaxis in immunocompromised patients.

Drug Interactions

  • Methotrexate: Interactions with NSAIDs and sulfonamides (reduce clearance).

  • Warfarin + 5-FU or capecitabine: Enhanced anticoagulation effect.

  • Cisplatin: Enhanced nephrotoxicity with aminoglycosides.

  • Anthracyclines: Additive cardiotoxicity with trastuzumab.

  • Imatinib: CYP3A4 substrate; interactions with azole antifungals, macrolides.

  • Checkpoint inhibitors: Potentiated toxicity with immunosuppressants.

Comparative Considerations

  • Traditional cytotoxic chemotherapy: Broadly affects dividing cells → high toxicity but still cornerstone for many cancers.

  • Targeted therapies: More selective, often oral, better tolerated, but resistance develops.

  • Immunotherapy: Durable responses in some cancers but unpredictable immune side effects.

  • Hormonal therapy: Crucial in hormone-sensitive tumors (breast, prostate).



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