Biomedical subjects
Publications and source records attributed to P Potier.
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Based on the structural differences of compounds isolated from various species of Taxus, this brief review suggests a biogenetic approach to taxol. This hypothesis could be of some help in the synthesis of this complex molecule exhibiting significant antitumor properties.
In order to compare the antineoplastic activities of taxol A, taxol B, a mixture of the two (taxol A 72%) and vinblastine, a human ovarian tumor serially transplanted into 104 female athymic mice was used. In the first experiment (11th passage), the antineoplastic activities of taxol A, taxol B and the mixture taxol AB were tested. The same dose was used in each case (12.5 mg/kg i.e. 1/20 of the evaluated LD50 value). It was administered subcutaneously for 5 consecutive days. Three courses of treatment were performed, with 2 rest periods of 1 week in between. All the taxol derivatives produced a statistically significant delay in the tumor growth. However, taxol B had the lowest chemotherapeutic response. In the second experiment (18th passage), different dose levels were administered (mixture 12.5 mg/kg/day x 4 - taxol A 8.8. mg/kg/day x 4 - taxol B 3.5 mg/kg/day x 4 - vinblastine 0.5 mg/kg/day x 2). For all the taxol derivatives 4 treatment courses with 3 rest periods of 4 days were used, and for vinblastine 4 treatment courses with 3 rest periods of 1 week. At the end of the second experiment, vinblastine, taxol A and a mixture of the two showed similar significant activity, whereas no objective antitumor response was observed following the taxol B treatment at the dose level chosen. The experimental results obtained clearly demonstrate that, in the taxane system, the greatest degree of antineoplastic activity can be attributed to taxol A.
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Since the discovery of Taxol and of its antitumor activity a number of chemical, pharmacological and clinical studies have been performed on this natural diterpene isolated from the genus Taxus. Because the extraction of Taxol from the bark is expensive, difficult and damaging to the Taxus species, alternative sources have been studied. To date, one of the most promising alternatives is the semisynthesis of Taxol from 10-deacetylbaccatin III, a renewable precursor found in the needles of the European yew tree, Taxus baccata. From this natural compound, a number of new active compounds bearing different substituents at carbons 2, 4, 5, 7, 10, 13, 2' and 3' have been prepared. Among the new substances, Taxotere (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol) was found to be one of the most potent in its interaction to the cellular target of antitumor taxoids: tubulin. The chemistry and structure-activity relationships of the antitumor taxoids are presented.