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Date of Award

1990

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Graduate School

First Advisor

Patrick Catania

First Committee Member

William Kehoe

Second Committee Member

Fuad M. Nahhas

Third Committee Member

Michael Mergener

Fourth Committee Member

Katherine Knapp

Abstract

Tumor necrosis factor is a cytokine which has specific, rapid cytolytic activity against susceptible animal tumors and human tumors in nude mice suggesting antitumor activity in humans. It has also been implicated as an important mediator of the lethal effects of endotoxic shock and cachexia of chronic infection. This phase I study aimed to investigate toxicity, tolerance and some metabolic effects of recombinant tumor necrosis reactor (rTNF) administered as a continuous infusion to cancer patients. Fourteen patients received treatment at two consecutive dose levels and dosages were administered on a microgram/m$\sp2$ basis. Patients were monitored closely for signs and symptoms of toxicity. Besides, several studies were conducted to investigate physiological and metabolic effects plus pharacokinetic behavior and therapeutic potential of rTNF administered to cancer patients. Systemic symptoms of mild fever, chills, and rigors were the most frequently seen evidence of rTNF toxicity at all dose levels. Reductions in WBC and platelet counts were observed regularly at the highest dose level, but none were clinically significant. No significant alteration in the biochemical parameters was found that could reflect some organ damage or reduced function even at highest dose levels. Elevations in C-reactive protein were observed in all patients at all dose levels, demonstrating an acute phase response of the body towards rTNF administration. Besides an elevation of serum ferritin and drop in serum iron at highest doses suggesting some type of protective mechanism against that rTNF insult. There was no change in heparin-releasable serum lipoprotein lipase levels despite increase in serum triglycerides, measured during a meal profile test, at highest doses of rTNF. This might suggest that the effects of rTNF on lipid metabolism may be directed more toward lipogenesis rather than increased lipolysis in peripheral adipocytes. No potential therapeutic effect of rTNF was observed in this advanced cancer opulation suggesting the need for altering dose regimens (with minimal toxicity possible), or use of combination or local therapy, or use of this agent in less advanced disease.

Pages

146

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