Treosulfan and gemcitabine

Excerpt

Contrary to the authors’ assertion, the paper by Terheyden et al. confirms the results of earlier in vitro studies, which suggested that low doses of treosulfan will be ineffective. The title is therefore misleading and the paper contains many other inaccuracies. Our in vitro papers (Myatt et al. 1997; Neale et al. 1999) showed enhancement of the cytotoxicity of treosulfan by gemcitabine in uveal melanoma cells obtained from the primary tumour. We used an arbitrary threshold to compare the sensitivity of the agents tested, equivalent to 50% inhibition of the ATP content of the cells across the range of concentrations tested (Neale et al. 1999). Our data showed that DTIC was inactive, in keeping with clinical results, and that treosulfan alone showed the best activity of any of the alkylating agents tested (6% with >50% inhibition) (Neale et al. 1999). This was modulated by gemcitabine, a cytidine analogue we postulated might inhibit repair of treosulfan-induced DNA damage, with 70% of tumours then showing >50% inhibition in the assay. It should be noted that the logarithmic kill hypothesis requires around 99% inhibition to produce a clinical response in six cycles. We were extremely careful to emphasise that these comparative figures would therefore not be expected to translate directly into clinical practice. Our papers simply suggested that treosulfan + gemcitabine might be more active in patients than other drugs and combinations tested, and stated that clinical trials were necessary. …