Rationale for Intralesional Valrubicin in Chemoradiation of Squamous Cell Carcinoma of the Head and Neck

Abstract

Objectives/Hypothesis: With some advanced squamous cell carcinomas (SCCs) of the head and neck, chemoradiation therapy may obviate the need for surgical intervention. However, both modalities are known to produce organ toxicities, and tumor insensitivity remains problematic. Thus there is a clear need for the development of new treatment strategies. Accordingly, preclinical studies to evaluate the use of valrubicin, a contact-safe, mechanistically novel antitumor agent, combined with low-dose radiation for the therapy of SCC have been conducted. Methods: The comparative in vitro antitumor activities of valrubicin with or without irradiation versus cisplatin were evaluated using human-derived sensitive and cisplatin-resistant SCC cell lines. A hamster cheek pouch model of SCC was used to assess the efficacy of weekly intratumoral valrubicin injections with and without concurrent low-dose irradiation. Results: Valrubicin cytotoxicity was found to be comparable in both sensitive and platinum-resistant cell lines and superior to cisplatin. The addition of minimally cytotoxic cell irradiation (300 -450 cGy) resulted in prolonged G 2 /M cell cycle arrest and a supraadditive increase in apoptotic cell death. In hamsters, once a week ؋ 3 intratumoral drug injections (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 cytoplasmic-localizing drug, to inhibit protein kinase C. Therapeutic use of valrubicin against SCC could provide for reduced radiation doses with consequent improved efficacy and reduction in host toxicity.

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

“…AD 32 (valrubicin) shares some features with AD 198, such as preferred localization in the cytosol and lack of topoisomerase inhibitory activity. Studies performed in animal models of human head and neck squamous cell carcinoma suggest that valrubicin may be a catalytic inhibitor of PKC (Wani et al, 2000). This is also indicated by the fact that valrubicin synergizes with sublethal doses of ionizing radiations in head and neck squamous carcinoma cells (Wani et al, 2000), a behavior shared with established PKC inhibitors like calphostin, staurosporine, and PKC-412 (Rocha et al, 2000).…”

“…Studies performed in animal models of human head and neck squamous cell carcinoma suggest that valrubicin may be a catalytic inhibitor of PKC (Wani et al, 2000). This is also indicated by the fact that valrubicin synergizes with sublethal doses of ionizing radiations in head and neck squamous carcinoma cells (Wani et al, 2000), a behavior shared with established PKC inhibitors like calphostin, staurosporine, and PKC-412 (Rocha et al, 2000). On the other hand, the valerate-free metabolite of AD 32 [Ntrifluoroacetyldoxorubicin (AD 41)] is a nuclear-targeted topoisomerase I/II poison whose activity may be hampered by resistance mechanisms typical of conventional anthracyclines.…”

Topical application of valrubicin has a beneficial effect on developing skin tumors

“…Also, in contrast to doxorubicin, valrubicin demonstrates binding to cytoplasmatic protein, a way valrubicin seems to explicate its effect (5,22). Valrubicin has been shown to inhibit growth of leukemia cells (23) and melanoma cells (24) and has proven efficient in systemic treatment of SCC of the head and neck (25). Currently, valrubicin is approved for the treatment of bladder cancer, where the therapeutic potential is achieved by contact to the cells of the bladder wall (1,26,27).…”

Anthracycline drug targeting: cytoplasmic versus nuclear – a fork in the road

“…At sub-cytotoxic doses, VLR synergizes with sub-lethal doses of ionizing radiation in head and neck squamous carcinoma cells to produce a 4-to 6-fold increase in the apoptotic index over cells exposed to either radiation or VLR alone. 95 Among the compounds thus far identified as producing synergy with ionizing radiation are a variety of PKC inhibitors including calphostin, staurosporine, and PKC-412. 96,97…”