title: Rationale for intralesional valrubicin in chemoradiation of squamous cell carcinoma of the head and neck.
abstract: OBJECTIVE
  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 G2/M cell cycle arrest and a supraadditive increase in apoptotic cell death. In hamsters, once a week x 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.
authors: Department of Otolaryngology--Head and Neck Surgery, University of Tennessee College of Medicine, Memphis 38163, USA.
authors: M K
authors: MK
authors: Wani
authors: Y
authors: Y
authors: Koseki
authors: R H
authors: RH
authors: Yarber
authors: T W
authors: TW
authors: Sweatman
authors: A
authors: A
authors: Ahmed
authors: S
authors: S
authors: Samant
authors: A
authors: A
authors: Hengesteg
authors: M
authors: M
authors: Israel
authors: K T
authors: KT
authors: Robbins
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D006224:Cricetinae; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D015552:Injections, Intralesional; D023421:Models, Animal; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C016163:valrubicin; D004317:Doxorubicin