Is photodecomposition more important than metabolic activation for the antitumor activity of dacarbazine (multiple letters)

Lev et al. (1) clearly demonstrate that the antitumor agent dacarbazine (DTIC) causes melanoma cells to secrete interleukin (IL)-8 and vascular endothelial growth factor (VEGF). The authors suggest that cytokine overexpression might render tumor cells resistant to DTIC, which is presently considered the reference drug for the treatment of malignant melanoma. The study has been entirely conducted using light-activated DTIC without considering that DTIC requires metabolic activation by liver microsomes to generate 5(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), which is responsible of the alkylation of nucleic acids (2). In particular, O6-methylaguanine is regarded as the major cytotoxic lesion produced by the active metabolite of DTIC (2). In fact, tumor cells expressing high levels of the O6-alkylguanine DNA alkyltransferase (AGT) are resistant to DTIC and to temozolomide, which spontaneously decomposes in aqueous solution to generate the methylating species MTIC (3, 4). Although the importance of light protection for DTIC, to avoid toxicity due to photodecomposition products, is still controversial, it is instead well established that the antitumor activity of DTIC is mainly the result of DNA methylation. Therefore, to assess whether IL-8 and VEGF expression in melanoma cells might limit the efficacy of DTIC, it would have been certainly more interesting to evaluate the influence of MTIC-induced DNA methylation rather than analyzing the effects of photodecomposition products, which might not substantially contribute to the antitumor effects of DTIC.