Plant-derived antineoplastic agents

Vinca alkaloids

The source of these alkaloids is the Madagascar periwinkle plant (Vinca rosea). Key representatives of the group are vincristine and vinblastine, which have a similar chemical structure. Their action is strictly tied to the M-phase of the cell cycle.

The molecular mechanism involves binding to tubulin and blocking its GTP-dependent polymerization. As a result, microtubules simply do not form, a defective mitotic spindle is created, and mitosis halts at the metaphase stage.

• Vincristine is actively used in pediatric oncology (acute lymphoblastic leukemia, Wilms tumor), as well as in Ewing sarcoma and lymphomas.
• Vinblastine is more commonly used in combination regimens (e.g., with cisplatin and bleomycin) for the treatment of metastatic testicular carcinoma and a number of solid tumors.

Taxanes

These compounds were originally isolated from the Pacific yew (Taxus brevifolia). The toxic properties of this plant were known even in antiquity—in Europe, yew cups were even used to poison drinks. The active cytotoxic substance is the alkaloid taxol.

Unlike periwinkle, paclitaxel and docetaxel bind to the $\beta$-subunit of tubulin and, conversely, stimulate its polymerization even in the absence of GTP and necessary proteins. Microtubules become excessively stable and lose the ability to depolymerize (disassemble). The cell fills with non-functional tubulin and loses the ability to divide.

Taxanes are in demand for the treatment of breast cancer, ovarian cancer, non-small cell lung cancer, and epithelial tumors of the head and neck.

Pharmacokinetics and the problem of resistance

All drugs of these two groups are administered exclusively intravenously. In the body, they are distributed quite widely, but taxanes do not cross the blood-brain barrier. Metabolism occurs in the liver with the mandatory participation of cytochrome P450 system enzymes, which requires dose adjustment when prescribing concomitant medications. Elimination occurs primarily via bile through the gastrointestinal tract.

The main reason for the development of tumor resistance to these plant agents is the hyperactivity of P-glycoprotein. This transport protein acts like a pump, expelling drug molecules out of the cell. For taxanes, an additional factor of resistance can be mutations in the structure of tubulin itself.

Safety profile and management of complications

Therapy with microtubule inhibitors is accompanied by a number of severe side effects. With the administration of vinca alkaloids, local reactions are possible, ranging up to tissue necrosis and phlebitis. Due to the massive destruction of tumor cell DNA, purines are released into the blood, which are oxidized to uric acid. To prevent this hyperuricemia, allopurinol is prescribed.

According to the classification in the study material, periwinkle drugs have a specific division of toxicity:

1. For vincristine, myelosuppression is most characteristic.
2. For vinblastine, neurotoxicity is typical (ataxia, paresthesias, reflex impairment).

When using taxanes, peripheral neuropathy and neutropenia frequently develop, requiring the administration of filgrastim. In addition, docetaxel causes fluid retention, and paclitaxel poses a risk of bradycardia and severe allergic reactions (strict premedication with a combination of dexamethasone and diphenhydramine is required).

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• The role of P-glycoprotein in the development of multiple drug resistance in tumors
• Combination chemotherapy regimens including cisplatin and bleomycin
• Mechanisms of peripheral neuropathy development during cytostatic therapy
• Features of drug metabolism by the cytochrome P450 system and drug interactions
• Historical aspects of using Pacific yew poisons

Other topics in the "Antineoplastic agents" section

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