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.
Highlights
As a new anti-cancer drug, paclitaxel has promising efficacy but considerable clinical limitations owing to issues of supply, solubility and toxicity
Synthesis of taxane analogues The synthesis of the taxane analogues (Figure 1) has been described in detail previously (Klein et al, 1994; Li et al, 1994)
Experimental and control taxane compounds were dissolved in ethanol and added to the tumour cells in 96-well microtitre plates
Summary
Synthesis of taxane analogues The synthesis of the taxane analogues (Figure 1) has been described in detail previously (Klein et al, 1994; Li et al, 1994). Paclitaxel was obtained from NaPro Biotherapeutics, Boulder, CO, USA. In vitro evaluation of anti-tumour compounds The in vitro potency of experimental and control taxanes was determined using a colorimetric assay to assess cell cytotoxicity as described previously (Chu et al, 1992). Tumour cell lines were maintained in RPMI-1640 plus 10% fetal calf serum. Experimental and control taxane compounds were dissolved in ethanol and added to the tumour cells in 96-well microtitre plates. The cells were exposed to compounds for 72 h. Cell viability was determined by MTT dye reduction using absorbency at 470 nm. The inhibitory concentration 50% (IC50) was determined as the drug concentration to produce 50% cell cytotoxicty
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