Topoisomerase Inhibitors and Antineoplastic Enzymes

Topoisomerase Inhibitors

• Topotecan and Irinotecan: Semi-synthetic drugs derived from a Chinese shrub (camptotheca), a newer class of chemotherapy drugs.
• Mechanism of Action: Bind to the DNA-topoisomerase I complex during the S phase, inhibiting proper DNA functioning by slowing and breaking DNA strands.
• Indications: Ovarian cancer, colorectal cancer, and small cell lung cancer.
• Administration: Injectable only.
• Adverse Effects: Stomatitis, hair loss, mild gastrointestinal upset. Irinotecan can cause indirect cholinergic effects (e.g., diarrhea, lacrimation, sweating) 2-10 days post-infusion. Bone marrow depression and cardiovascular toxicity (pulmonary embolism, stroke, heart attack) are also possible.
• Special Note (Etoposide): Diluent may cause hypotension, and use in testicular cancer may increase orthostatic hypotension risk.

Antineoplastic Enzymes

• Pegaspargase and Asparaginase (Kidrolase, Erwinase): Enzymes synthesized from bacterial cultures (E. coli) using recombinant DNA technology.
• Mechanism of Action: Inactivate cells' ability to synthesize asparagine, a crucial amino acid for DNA synthesis and cell survival during the G1 phase.
• Indications: Lymphocytic leukemia only.
• Administration: Injectable only.
• Adverse Effects: Allergic reactions to Pegaspargase are common, along with impaired pancreas function, hyperglycemia, and pancreatitis.

Cell Cycle Non-Specific Drugs

• Broad Categories: Alkylating drugs and cytotoxic antibiotics are cell cycle non-specific, meaning they are cytotoxic to cancer cells at any stage of the cell cycle.
• Emergence: Chemotherapeutic agents emerged in the 1940s. The first, an alkylating drug, was developed from mustard gas (nitrogen mustard).

Alkylating Drugs

• Mechanism of Action: Alkylation (transfer of an alkyl group) leads to abnormal DNA bonds, causing DNA damage that disrupts cell reproduction and induces cell death. The degree of alkylation varies by drug.
• Indications: Various solid and circulating cancers.
• Categories:
  • Classic alkylators (nitrogen mustards, like cyclophosphamide, chlorambucil, isofamide, and melphalan)
  • Nitrosoureas (like carmustine, lomustine, and streptozocin)
  • Miscellaneous alkylators (like busulfan, carboplatin, cisplatin, dacarbizinem, oxaplatin, procarbaine hydrochloride, and temozolimide)
• Adverse Effects: Similar dose-limiting effects as cell-cycle specific drugs (e.g., nephrotoxicity, neurotoxicity, bone marrow suppression, ototoxicity, pulmonary fibrosis), with IV extravasation risks (requiring sodium bicarbonate as antidote) and drug interactions possible.

Cytotoxic Antibiotics

• Source: Natural and semi-synthetic substances derived from the mould Streptomyces.
• Mechanism of Action: "Intercalation" (inserting molecules in between DNA strands) blocks DNA synthesis. They also inhibit topoisomerase II, cause DNA strand breaks, and generate free radicals, all contributing to cell death.
• Indications: Solid tumors and hematological cancers.
• Types:
  • Anthracyclines: Daunorubicin, doxorubicin, epirubicin, idarubicin, valrubicin
  • Other cytotoxic antibiotics: Bleomycin (cell cycle specific), dactinomycin, mitomycin, mitoxantrone (also cell cycle specific)
• Administration: Injection only (central line recommended for some, like daunorubicin and dactinomycin).
• Adverse Effects: Hair loss, nausea and vomiting; bone marrow suppression, hepatotoxicity, bleomycin-related pulmonary toxicity (fibrosis, pneumonitis), anthracycline-related heart failure/cardiomyopathy, and numerous drug interactions (especially with digoxin).

Hormonal Antineoplastics

• Mechanism of Action: Block sex hormone receptors or administer opposing-effect hormones to hinder cancer cell growth.
• Therapeutic Use (Breast Cancer): Estrogen modulates estrogen receptor-positive breast cancer growth and blocking its production/utilization slows tumor growth.
• Drugs:
  • Estrogen Receptor-positive tumor drugs: Tamoxifen, Toremifene
  • Selective estrogen receptor modulators (SERMs): Anastrozole, exemestane, letrozole. Aromatase inhibitors
• Prostate Cancer: Androgen deprivation therapy (blocking testosterone production or use) via drugs like bicalutamide, flutamide, and estramustine.
• Adverse Effects: Menopause-like symptoms (hot flashes, night sweats, irregular periods), osteoporosis, potential endometrial cancer risk (tamoxifen), fatigue, infertility/impotence (men), blood clots, and cardiovascular risk.

Targeted Drug Therapy

• Concept: Aims to target specific molecules involved in cancer cell growth, sparing normal cells.
• Examples: Imatinib (tyrosine inhibitor), vorinostat (histone deacetylase inhibitor).
• Immunotherapy: Uses the body's own immune system to target and destroy cancer cells.
• Types:
• Hematopoietic factors can enhance immunity compromised by chemotherapy
• Monoclonal Antibodies (MABs)
• Angiogenesis Inhibitors (block tumor blood vessel growth - stopping nutrition delivery to tumor)
• Interferons and interleukin-2
• Immunostimulants
• CAR-T cells (patient's own T-cells modified to attack cancer cells - revolutionizing treatment of some leukemias).

Explore the mechanisms, indications, and side effects of topoisomerase inhibitors such as Topotecan and Irinotecan, as well as antineoplastic enzymes like Pegaspargase. This quiz delves into their use in cancer therapy and administration methods. Test your knowledge on these critical chemotherapy agents!