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Book Summary:
Cancer has been afflicting populations worldwide throughout recorded history. Despite making significant progress in-the treatment of cancer, the prognosis for most cancer types remains grim. Thus, novel approaches for treating this disease are still needed. Pharmacogenomics, a branch of pharmacology particularly relevant to the cancer research field, is the study of how variations in the genome affect response to pharmaceutical agents and influence biological pathways and processes, including the pharmacokinetics, pharmacodynamics, efficacy, and toxicity of a drug. The observations detailed in this dissertation suggest that, by utilizing a pharmacogenomic approach, it is possible to design novel therapies or regimens to ultimately treat patients with highly lethal cancers, specifically glioblastoma multiforme (GBM) and pancreatic andenocarcinoma (PAC). We achieved this objective through validation of gene expression quantitation methods and by focusing on drug-metabolizing enzymes, such as thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase, which have been shown by us and others to affect therapeutic response, efficacy, and toxicity of 5-fluorouracil-based agents such as capecitabine (CAPE; a novel, orally administered 5-fluorouracil prodrug). Molecular analysis demonstrating elevated TP levels in GBM, as well as the up-regulation of TP with radiotherapy in glioma xenografts (possibly as a result of cytokine mediation), provided the rationale to examine CAPE chemoradiotherapy for GBM. Analyses of PAC, which has a molecular profile similar to that of GBM, also suggested CAPE use; however, radiotherapy did not increase TP, as evidenced by studies in xenografts and clinical samples. Nevertheless, CAPE-radiotherapy demonstrated synergistic antitumor efficacy in PAC xenografts. These results provided the foundation for the design and realization of 2 Phase-I clinical trials conducted at our institution, which demonstrated low toxicity of CAPE-radiotherapy in both PAC and GBM patients. Additionally, in GBM patients, one complete remission was documented. These studies will be fundamental in establishing the rationale to further develop clinical studies and protocols. In summary, the observations detailed herein provide compelling evidence that utilizing a pharmacogenomic approach to design CAPE chemoradiotherapy treatment regimens for PAC and GBM patients is a rational choice and provides a feasible and a potentially effective method for improving response to chemotherapy, in terms of both reduced toxicity and enhanced efficacy. |
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