Many of the anti-cancer drugs that are used in clinical medicine are of natural origin.

VINCA ALKALOIDS

Compounds with marked anti-tumour activity have been extracted from the periwinkle plant. Vinblastine and vin-cristine have been widely used, both as single agents and in combination with other drugs. Vinca alkaloid analogues have been prepared either by functional transformation (vindesine, desacetylvinblastine-amide) or, more recently, by hemisynthesis (vinorelbine, 5-noranhydrovinblastine). Although these compounds are all chemically related, differ­ences have been observed in anti-tumour activity and tox-icity. The mode of action of vinca alkaloids is yet to be completely understood, but they act as mitotic spindle poi­sons, which impair chromosomal segregation during mitosis. Microtubules are essential for normal cellular function and are involved in the maintenance of cell shape, mobility, adhe­sion and intracellular integrity, as well as having a role in the formation of the mitotic spindle during proliferation.

Vinblastine is active in haematological cancers and in testicular and breast cancer. Vincristine is also active in these tumours, in addition to Wilm’s tumour, Ewing’s sarcoma, neuroblastoma, hepatoblastoma and embryonal rhabdomyosarcoma. The anti- tumour activity of vindesine is similar to that of vinblastine and vincristine, whereas vinorelbine is particularly active in non-small-cell lung can­cer, breast cancer, ovarian cancer and Hodgkin’s disease. Vincristine and vindesine administration can cause neuro­logical toxicity characterized by a decrease in the deep ten­don reflexes, paraesthesias, constipation, myalgias, muscle weakness and paralytic ileus. Vinblastine generally pro­duces haematological toxicities. Vinorelbine neurotoxicity is usually very mild, with only rare cases of paraesthesia or paralytic ileus being reported. Experimental evidence sug­gests that this may be due to the capacity of vinorelbine to bind to mitotic microtubules, rather than axonal micro­tubules. Clinical pharmacokinetics of vinca alkaloids are characterized by large distribution volume, high systemic clearance and long terminal half-life, although there are sig­nificant differences between analogues.

TAXANES

Paclitaxel (Taxol) is a chemically complex molecule first isol­ated from the bark of the Pacific Yew tree Taxus brevifolia in the early 1970s. Its unique mechanism of action was not elicited for almost a decade and its importance as a major advance in the treatment of malignant disease was not recog­nized until 1989. Paclitaxel interferes with cell division by manipulating the molecular regulation of the cell cycle. In the presence of paclitaxel, polymerization of subunits of tubulin occurs, and the formed microtubules resist dis­assembly, thus shifting the equilibrium towards micro-tubule formation. Disruption of this equilibrium interferes with cell division and normal cellular activities involving microtubules.

The pharmacokinetic behaviour of paclitaxel was stud­ied during the early-phase trials in the 1980s. These studies used infusional schedules of between 1 and 24 hours and optimally modelled the concentration/time profile using a triphasic model. In general, administered dose was propor­tional to the area under the time/concentration curve (AUC). However, shorter infusions of paclitaxel (3 hours) seem to demonstrate non-linearity, and the important implication for this feature is that small dose de-escalations may result in a disproportionate lowering of the AUC, with subsequently decreased anti-tumour activity. Paclitaxel is 90 per cent bound to plasma proteins, but this is readily reversible and results in rapid elimination of the drug. Renal excretion is negligible, and no renal metabolites have been identified. There may be significant hepatic metabolism, and various studies are in progress to look at the effects that other drugs that use the cytochrome P450 pathway may have on the pharmacological behaviour of paclitaxel.

Administration of paclitaxel is associated with allergic hypersensitive reactions ranging from acute anaphylaxis and hypotension to flushing, rashes and urticaria. Indeed, development of this agent was almost halted in the early stages due to the severity of these reactions. However, the instigation of a premedication regimen consisting of corti-costeroids and H1/H2 blockers has significantly reduced the incidence of allergic reactions from 20 per cent to 3 per cent. Although the formulation of paclitaxel in Cremophor EL® (due to its limited aqueous solubility) may be respon­sible for the hypersensitivity phenomena, some contribu­tion of paclitaxel itself is possible, as hypersensitivity reactions also occur with the semisynthetic analogue doc-etaxel formulated in Tween-80.

Leukopenia is the dose-limiting toxicity, and thrombo-cytopenia is rare. Myelosuppression occurs early and is associated with a rapid recovery, allowing treatment to proceed on a 3-week cycle. Neurotoxicity occurs with higher cumulative doses of paclitaxel, and with higher doses per course. This is mainly a sensory neuropathy and manifests in a ‘glove and stocking’-type distribution. It is at least partially reversible with time. Many cardiac arrhyth­mias have been reported with paclitaxel administration, ranging from asymptomatic bradycardia to various degrees of heart block and atrial/ventricular tachyarrhythmias. Other frequently reported toxicities include alopecia (uni­versal), fatigue and arthralgia/myalgia. Indications for use include breast cancer (anthracycline-pretreated), ovarian cancer, and non-small-cell lung cancer.

Docetaxel (Taxotere) is another member of the taxoid family. There is pre-clinical evidence to suggest that doc­etaxel may be superior to paclitaxel. Docetaxel has been shown to be more potent (up to five-fold) in vitro than paclitaxel with regard to the promotion of tubulin poly­merization and inhibition of depolymerization. In a direct comparison with paclitaxel in a large number of freshly explanted tumours (including breast, ovarian, lung and colorectal tumours), docetaxel was found to have ai least equivalent cytotoxicity, but with incomplete cross-resistance. Docetaxel also had a longer residence time, accumulated at higher concentrations within cells and demonstrated a superior therapeutic index in vivo. Clinical studies have confirmed the presence of incomplete cross-resistance with paclitaxel, reporting activity for docetaxel in paclitaxel-resistant metastatic breast cancer.

Docetaxel pharmacokinetics following a 1-hour infu­sion demonstrate that the plasma elimination at the high­est doses follows a triphasic decay, with a terminal half-life of 13.5 hours and a plasma clearance of approximately 21 L/h per m². The AUC increases linearly with the dose and correlates with the percentage decrease of neutrophils. Less than 10 per cent of the administered dose is excreted unchanged in the urine. The recommended dose as a single agent is 100mg/m² given as a 1-hour intravenous infusion. Patients that have been heavily pretreated or have abnor­mal hepatic function should receive a reduced dose. The most frequent toxicity is an early, reversible, non-cumulative neutropenia, which may be associated with concurrent infections. Anaemia has also been observed. Hypersensitivity reactions occurred in 25 per cent of patients who were unpremedicated with corticosteroids, and these generally occurred on the first course, within a few minutes of the start of the infusion. Premedication with corticosteroids has reduced the incidence of hyper­sensitivity reactions to less than 5 per cent. Cutaneous reactions occur, characterized by a rash, mainly on the extremities (but also localized eruptions on arms, face or thorax), and are occasionally associated with pruritus. These are usually transient and resolve prior to the next course of treatment. Less frequently, desquamation is observed. Nail changes (onycholysis, hypo/hyperpigmen-tation) are also seen. A fluid-retention syndrome, charac­terized by asymptomatic weight gain and/or oedema (and, less often, pleural, peritoneal or pericardial effusions), has been observed. This generally starts in the lower extrem­ities and at cumulative doses of 400 mg/m². The pathogen-esis of this condition is incompletely understood, but appears reversible on cessation of docetaxel treatment and can be significantly reduced by premedication with dexa-methasone. Mild degrees of this syndrome can be treated adequately by diuretic therapy, but it is recommended that patients with severe oedema should not continue with doc­etaxel. Clinically significant cardiac events occurred in less than 2 per cent of all patients treated, and are not clearly related to docetaxel administration. Other significant tox-icities encountered are alopecia, hepatotoxicity (mild, reversible transaminase elevations), mucositis, diarrhoea, arthralgia/myalgia and peripheral neuropathy (sensory and motor). Emesis is generally mild and easily treated with 5HT3 antagonists.

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