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Experimental dacarbazine antitumor activity and skin toxicity in relation to light exposure and pharmacologic
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.
Insights
Light exposure after dacarbazine (DTIC) injection increases skin toxicity in mice. While light does not affect DTIC’s antitumor activity or cytotoxicity, patients should avoid intense light post-injection to minimize adverse effects.
Area of Science:
- Pharmacology
- Oncology
- Dermatology
Background:
- Dacarbazine (DTIC) is a chemotherapy agent with known antitumor properties.
- Previous in vitro studies suggested light exposure could enhance DTIC's toxicity and efficacy.
- The in vivo effects of light exposure on DTIC's therapeutic and toxicological profile remained unclear.
Purpose of the Study:
- To investigate whether light exposure enhances dacarbazine's antitumor activity or local toxicity in vivo.
- To evaluate the impact of light on DTIC's cytotoxicity in cancer cell lines.
- To assess potential antidotes for DTIC-induced skin ulceration.
Main Methods:
- Mice with implanted adenocarcinoma were treated with light-exposed or protected DTIC solutions.
- In vitro clonogenic assays were performed on L1210 leukemia and CHO cells exposed to DTIC with or without light.
- Mice received intradermal DTIC injections, with some groups exposed to light post-injection; skin ulceration was assessed.
Main Results:
- Light exposure did not significantly alter DTIC's antitumor efficacy in mice or its cytotoxicity in vitro.
- Intradermal DTIC caused dose-dependent skin ulceration in mice.
- Post-injection light exposure significantly increased DTIC-induced skin toxicity; sodium thiosulfate showed some protective effect.
Conclusions:
- Dacarbazine (DTIC) synergizes with light in vivo to increase local skin toxicity, not antitumor efficacy.
- Patients receiving DTIC should avoid intense light exposure after administration to mitigate skin toxicity.
- Precautions to shield DTIC solutions during preparation or administration are likely unnecessary.