SAFETY OF IN-VIVO ADENOVIRUS-MEDIATED THYMIDINE KINASE TREATMENT OF ORAL-CANCER

Background: Adenovirus-mediated transfer of the herpes simplex virus t hymidine kinase gene (th) is one of the most effective gene therapy st rategies for solid tumors in experimental animal studies. Foundational animal studies in an oral cancer model have demonstrated significant and tumor effects and improved animal survival using this treatment st rategy. Objective: To assess the safety of adenovirus-mediated transfe r of the herpes simplex virus th gene for the treatment of oral cancer . Design: Oral tumors were established in C3H/HeJ mice and were treate d with tk followed by systemic ganciclovir administration. Polymerase chain reaction amplification techniques were used to screen local surr ounding tissues and distant organs for the presence of the adenoviral construct. Microscopic examination of the tissues was performed to det ermine the cytopathic effects of the vector. Blood samples were obtain ed from the animals to test for liver, renal, and bone marrow function after treatment. Results: The adenoviral vector was present in the li vers, lungs, and kidneys of animals treated with the maximal single in jection dose of 2 x 10(9) plaque forming units (pfu). No vector was no ted systemically after delivery of an equally effective low dose of 1 x 10(8) pfu. Microscopic examination revealed no cytopathic effects in distant organs despite the presence of vector. Results of liver and r enal function tests revealed no differences between treated and contro l animals. There was no statistical difference in white blood cell cou nt, hematocrit, or platelet count between animals treated with gancicl ovir and control animals. Conclusions: Based on these results, the dir ect delivery of adenovirus-tk followed by ganciclovir administration a ppears both efficacious and safe in an animal model. However, serum ev aluation for adenovirus vector and screening organ function studies sh ould be included in human protocols using this gene therapy scheme.