PACLITAXEL AS A RADIOSENSITIZER - A PROPOSED SCHEDULE OF ADMINISTRATION BASED ON IN-VITRO DATA AND PHARMACOKINETIC CALCULATIONS

Paclitaxel is efficacious against many human cancers, Because it block s cells at the radiosensitive G2-M interface, paclitaxel has been inve stigated as a radiosensitiser. The results have been equivocal and som ewhat contradictory. It is impossible to obtain proper pharmacokinetic calculations, aimed at obtaining maximum cytotoxicity and/or radiosen sitisation, without knowing (i) how long the drug must be in contact w ith the cells, (ii) how long the effect lasts after the drug is remove d from the cellular environment, (iii) whether the drug acts as a radi osensitiser even when, like ca's-platinum, it is added after the radia tion and (iv) what the minimum quantity of drug in the cellular enviro nment: is required for both chemotoxicity and radiosensitisation. The present work addresses the above questions. Two radioresistant tell li nes of human origin were used, A375 melanoma and S549 lung carcinoma, in a clonogenic assay where only colonies with 50 or more cells were c ounted, For the irradiation, 6 MV X-rays were used. Any G2-M block was quantified: by cell cycle kinetics analysis. From the results, a simu lation of pharmacokinetics was conducted to calculate the schedule of administration of paclitaxel most likely to achieve and maintains sign ificant chemotoxocity and radiosensitisation. The minimum concentratio n of paclitaxel for measurable cytotoxicity was 3 nM for both cell lin es, but the drug was more toxic to the A549 cells. The minimum concent ration for measurable radiosensitisation was 3 nM for A375 and approxi mately 0.1 nM far A549, but whereas above 3 nM the radiosensitivity in creased in A375, it decreased above 1 nM for A549. A minimum of 18 h i ncubation with the drug was necessary for measurable effects and the r adiosensitising effects were lost soon after its removal. There was no radiosensitisation if paclitaxel was added after the radiation, and, at the minimum effective concentrations, it caused only a minor and tr ansient G2-M black. The pharmacokinetic calculations predict that 15 m g/m(2) paclitaxel given as a 1 h infusion 5 days/week for 3 weeks duri ng the radiotherapy should achieve both cytotoxicity and radiosensitis ation. The mechanism of radiosensitisation by paclitaxel at the concen trations suggested by our results does nor appear to be via a G2-M bla ck and is probably concentration dependent. The results imply that low -dose, daily infusions of paclitaxel for as long as possible during a course of radiotherapy are more likely to result in radiosensitisation and prolonged cytotoxicity than high-dose infusions given once a week . (C) 1997 Elsevier Science Ltd.