Rationale for intralesional valrubicin in chemoradiation of squamous cell carcinoma of the head and neck

Objectives/Hypothesis: With some advanced squamous cell carcinomas (SCCs) o f the head and neck, chemoradiation therapy may obviate the need for surgic al intervention. However, both modalities are known to produce organ toxici ties, and tumor insensitivity remains problematic, Thus there is a clear ne ed for the development of new treatment strategies. Accordingly, preclinica l studies to evaluate the use of, valrubicin, a contact-safe, mechanistical ly novel antitumor agent, combined with Low-dose radiation for the therapy of SCC have been conducted. Methods: The comparative in vitro antitumor act ivities of valrubicin with or without irradiation versus cisplatin were eva luated using human-derived sensitive and cisplatin-resistant SCC cell lines . A hamster cheek pouch model of SCC was used to assess the efficacy of wee kly intratumoral valrubicin injections with and without concurrent low-dose irradiation. Results: Valrubicin cytotoxicity was found to be comparable i n both sensitive and platinum-resistant cell lines and superior to cisplati n. The addition of minimally cytototxic cell irradiation (300-450 cGy) resu lted in prolonged G(2)/M cell cycle arrest and a supraadditive increase in apoptotic cell death. In hamsters, once a week x 3 intratumoral drug inject ions (3, 6, or 9 mg) were growth inhibitory; however, when valrubicin (6 mg ) was combined with minimally cytotoxic irradiation (150, 250, or 350 cGy) significant tumor shrinkage was observed, Conclusions: Valrubicin produces supra-additive effects against SCC when combined with low-dose irradiation. This effect appears to correlate with the ability of valrubicin, a cytopla smic-localizing drug, to inhibit protein kinase C. Therapeutic use of valru bicin against SCC could provide for reduced radiation doses with consequent improved efficacy and reduction in host toxicity.