Abstract
Expression of murine interleukin 3 gene in murine fibrosarcoma cells (NFsa-IL3) did not alter their survival to taxol treatment in vitro. However, NFsa-IL3 tumors established in vivo were much more sensitive to taxol than was the parental tumor. Administration of 60 mg/kg of taxol did not have any effects on the growth kinetics of NFsa tumors, but NFsa-IL3 tumors could be cured and developed long-term immunity. Examination of the molecular changes following taxol treatment indicates that TNF-αand iNOS production by tumor associated macrophages (TAMs) could be responsible for this effect. We found that expression of the IL-3 gene within tumors altered their responses to TNF-α and NO. NFsa cells were resistant to the cytotoxic effect of TNF-α and NO, but Nfsa-IL3 cells were sensitive to the killing of TNF-α and NO. Furthermore, taxol could stimulate the expression of TNF-α and iNOS by cells from a macrophage cell line (RAW 264.7) and TAMs. TAMs from NFsa-IL3 tumors were better primed for TNF-α and iNOS production than those from NFsa tumors. This suggests that taxol-induced TNF-α and NO production by TAMs could mediate the growth inhibitory effects in IL-3 gene-transduced tumors. This study indicates that combining gene immunotherapy could potentate the taxol efficiency for some taxol-resisant tumors.