Clinical, toxicological and pharmaceutical aspects of the antineoplastic drug taxol: A review

Abstract Taxol, a diterpene alkaloid isolated from the bark of Taxus brevifolia , has a unique mechanism of action. The drug promotes the formation of microtubule polymers in a cell, by reversibly and specifically binding the β-subunit of tubulin. Taxol is administered intravenously by a 3–24-hour infusion at 3-week intervals. Myelosuppression, especially neutropenia, appears to be the dose limiting toxicity in solid tumours at 200–250 mg/m 2 . Furthermore, side effects such as sensory neurotoxicity (with typical numbness, tingling and painful paraesthesiae in the extremities), diarrhoea and alopecia appear frequently. Mucositis appears to be the non-haematological dose limiting side effect at 390 mg/m 2 that has been determined in patients with leukaemia. Hypersensitivity reactions, which have been fatal in individual cases, might be schedule dependent. Furthermore, antiallergic prophylaxis must be given, although this precaution might not be considered to be fully protective. Phase I studies performed with combinations of taxol and cisplatin, doxorubicin or cyclophosphamide have indicated the feasibility of these regimens and show promise for future investigations. Addition of granulocytecolony stimulating factor (G-CSF), aimed at modulating myelosuppressive toxicity, showed in Phase I studies that the taxol dose could be increased to 250 mg/m 2 , with peripheral neuropathy as the dose limiting toxicity. In Phase II studies, taxol has been shown to be effective, including producing complete tumour remission, in advanced drug refractory ovarian carcinoma (19%–36% response rate), previously treated patients with metastatic breast carcinoma (27%–62% response rate), advanced non-small lung cancer (21%–24% response rate), advanced small cell lung cancer (37% response rate) and advanced head and neck cancer (34% response rate). Taxol was less effective in metastatic melanoma (12%–14% response rate, with a few complete remissions) and showed minimal activity in adenocarcinoma of the gastrointestinal tract. Renal cell carcinoma appeared to be unresponsive. The main constraint of this drug is its scarceness and difficulties of supply; therefore the search for alternative sources and the development of semisynthetic analogues such as taxotere (docetaxel) might be promising for the future.