In this renewal project as part of our effort to improve the treatment of patients with soft tissue sarcoma, we plan to utilize the information obtained in the past 5-6 years, to begin to select patients for specific treatments, based upon the genotype and phenotype of the tumor. This project involves the close collaboration and interaction of the other projects in this grant. Project I will afford the opportunity to obtain a sufficient member of fresh tumor samples for correlative studies and initiate patient trials. Analysis of STS cell lines and fresh tumor samples are carried out in close collaboration with project II, and project (synovial cell sarcomas). Specifically, we plan to continue to evaluate specific E2F forms (E2F2, E2F4) as transcriptional regulators for chemotherapeutic target genes (thymidylate synthase, dihydrofolate reductase, ribonucleotide reductase thymidine kinase), and the effects of up-regulation of these transcription factors on chemosensitivity using drugs that target these enzymes. In collaboration with Dr. C. Cordon-Cardo, we will carry out a detailed analysis of target genes for certain chemotherapeutic agents, and expression of genes involved in cell cycle control in soft tissue sarcoma cell lines (n=12), and will correlate these measurements with chemosensitivity. We will in parallel, carry out similar experiments in fresh STS samples and develop treatments that target a specific profile. We have tentatively generated four different treatment regimens; doxorubin treatment for tumors lacking functional pRb (with or without mutant p53), that also are MDR and MPR negative; ralitrexed )Tomudex ) treatment for patients with low levels of TS; L-alanosine with or without 5-deoxyadenosine for patients lacking meththioadenosine phosphorylase (associated with p16 deletions), and trimetrexate plus concomitant leucovorin, for patients demonstrating low levels of reduce folate carrier expression.
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