Determination of a Pain Substance Produced by the Photodegradation of Dacarbazine

Abstract

The anticancer drug, dacarbazine, is known to be photosensitive, and its photode-gradation products have been pointed out as the causes of side effects including local venous pain of injection site. In this study, we attempted to clarify the causative sub-stance of pain after photodegradation of dacarbazine. We synthesized five photodegrada-tion products of dacarbazine dimethylamine, 5-diazoimidazole-4-carboxamide (Diazo-IC), 4-carbamoylimidazolium-5-olate, 4-carbamoy1-2-(4-carbamoylimidazol-5-ylazo) imidazolium-5-olate and 2-azahypoxanthine, and examined pain reactions induced by these substances in mice. Mice were intraperitoneally administered each photodegrada-tion product, then number of stretching reactions or writhing reactions as types of pain behaviors was counted. Only Diazo-IC clearly induced the pain reactions in mice in a concentration-dependent manner the other products caused no pain reaction. The pain threshold of Diazo-IC in mice was estimated at between 0.1 mg/ml and 0.2 mg/ml. While diclofenac sodium significantly reduced acetic acid-induced pain reactions in mice, it did not influence the reactions induced by Diazo-IC. This result suggests that Diazo-IC-induced pain reactions represent a different mechanism from acetic acid-induced inflam-matory pain. Degradation rate constant of 0.1 mg/ml of dacarbazine solution was 10 times larger than 1 mg/ml of dacarbazine. Dacarbazine solution for drip infusion should be sufficiently shielded from light.