title: Experimental dacarbazine antitumor activity and skin toxicity in relation to light exposure and pharmacologic antidotes.
abstract: Decarbazine (DTIC) is reported to exhibit enhanced clinical toxicity and increased antitumor activity in vitro when exposed to light. Since it was unclear whether light exposure enhanced DTIC antitumor activity or local toxic effects in vivo, a series of experiments was performed in mice given DTIC solutions exposed to light for 2 hours at room temperature. Adenocarcinoma 07/A was implanted by trocar in adult female BALB/c mice. DTIC (50 and 100 mg/kg) was given ip three times per week for 2 weeks. Both drug doses significantly inhibited tumor growth. However, there was no significant difference between light-exposed and -protected drug treatments. In vitro clonogenic assays in L1210 leukemia and Chinese hamster ovary (CHO) cells demonstrated that DTIC cytotoxicity was not increased with light exposure (0.8 J/m2/sec). Both cell lines showed a dose-response relationship to DTIC after 1- or 6-hour exposures in the presence or absence of light. Normal dehaired BALB/c mice were given single intradermal injections of 0.5, 1.75, 5.0, or 10 mg of DTIC in 0.05 ml of saline. Dose-dependent skin ulceration was produced at the 1.75-, 5.0-, and 10.0-mg dose levels. Again, there was no consistent statistical difference in skin ulceration between treatments using light-exposed and -protected DTIC vials. However, when mice were exposed to light following intradermal DTIC, increased skin toxicity was produced (P less than 0.05 by Student-Neuman-Keuls multiple range test). A number of potential local antidotes to DTIC skin ulceration were found to be ineffective. These included: L-cysteine, dimethyl sulfoxide, hyaluronidase, hydrocortisone, and 0.9% saline. Sodium thiosulfate (0.3 M) significantly reduced DTIC skin ulcers as did pre-exposure of DTIC to S-9 rat liver enzymes and NADPH. Neither mild skin heating nor cooling reduced DTIC ulcerations. DTIC appears to synergize with light in vivo to produce increased toxicity. Patients receiving DTIC should avoid intense light exposure after drug injection. However, elaborate precautions to prevent light exposure of DTIC solutions during preparation or injection appear to be unnecessary.
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D003606:Dacarbazine / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008027:Light / Q000009:adverse effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010777:Photochemistry; D012883:Skin Ulcer / Q000139:chemically induced*; D012996:Solutions; D014410:Tumor Stem Cell Assay
chemical_list: D000931:Antidotes; D012996:Solutions; D009249:NADP; D003606:Dacarbazine