A early hypothesis of nutritional therapy in cancer management was if host nutritional status could be maintained or improved, then host survival should also improve. Several clinical trials were designed to test this hypothesis and found that total parenteral nutrition (TPN) did not increase the survival of patients with various neoplastic diseases treated with systemic chemotherapy. The failure of aggressive nutritional therapy to improve patient survival may be attributed to the competition of host and tumor tissues for nutrients. While TPN can maintain or improve host nutritional status, tumor consumption of nutrients can result in progressive tumor growth, leading to early host demise as suggested by some investigators. Although TPN- induced tumor growth in man has not been observed, recent evidence suggests that TPN may stimulate tumor growth. Because polyamine biosynthesis is necessary for cell proliferation, our finding that increased erythrocyte polyamine levels appearing in cancer patients receiving TPN and not in noncancer patients treated similarly suggested enhanced tumor growth. Further studies are needed to provide direct evidence that TPN-induced increases of RBC polyamines are associated with measurable accelerated tumor growth. A preliminary study has shown that TPN stimulates tumor growth during the plateau phase of its Gompertzian curve. Controlled studies are necessary to determine if this increased tumor growth is associated with increased RBC polyamine levels. The polyamine biosynthetic pathways may be an important focus for designing therapeutic manuvers that selectively divert nutrients to host tissues and away from neoplastic cells. The hypothesis is that administration of polyamine inhibitors during TPN may inhibit tumor utilization of nutrients and improve host nutrition. Difluoromethylornithine (DFMO) is a specific irreversible inhibitor of ornithine decarboxylase and its effect on host-tumor competition for nutrients will be studied.
The specific aims of this study are a) to determine if TPN will produce significant increases of RBC polyamine levels and tumor size during the nonexponential phase of growth, b) to determine if the administration of DFMO during TPN improves host utilization of nutrients while inhibiting tumor growth, and c) determine if DFMO in combination with cytotoxic chemotherapeutic agents will produce tumor regression further improving host utilization of exogenous nutrients.
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