Abstract
Two 9-dihydrotaxane analogues were synthesised and tested for in vitro potency and in vivo efficacy against murine and human tumour xenografts in mice. The in vitro potency of 9-dihydrotaxol (9-DH-t) and 10-deacetyl-9-dihydrotaxol (10-DeAc-9-DH-t) was generally less than that of paclitaxel against human and murine tumour cells. However, both analogues were at least 20-fold more soluble than paclitaxel in water. The analogues yielded cure rates > or = 60% against human MX-1 solid tumour xenografts in mice, compared with a cure rate of 10% for mice treated with paclitaxel. Both of the analogues were more effective than paclitaxel for treatment of murine M109 solid tumour in mice. 10-DeAc-9-DH-t was as effective as paclitaxel against murine B16 ascites tumour, while 9-DH-t was less effective. Both 10-DeAc-9-DH-t and 9-DH-t were demonstrably less toxic than paclitaxel. At equal dosages 9-DH-t produced serum concentrations greater than paclitaxel, while 10-DeAc-9-DH-t yielded serum concentrations less than paclitaxel. However, the decrease in toxicity of 9-DH-t and 10-DeAc-9-DH-t allowed a 4-fold increase in daily dosage. These two 9-dihydrotaxane analogues yielded favourable preclinical data and demonstrated good potential for further development.
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Alder, J., Jarvis, K., Marsh, K. et al. Preclinical in vivo efficacy of two 9-dihydrotaxane analogues against human and murine tumours. Br J Cancer 73, 560–564 (1996). https://doi.org/10.1038/bjc.1996.98
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DOI: https://doi.org/10.1038/bjc.1996.98
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