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Systemic Alkalinization Inhibits the Ability of Flavone Acetic Acid to Augment Natural Killer Activity, Induce Cytokine Gene Expression, and Synergize with Interleukin 2 for the Treatment of Murine Renal Cancer¹

Laboratory of Experimental Immunology, Division of Cancer Treatment, NCI-FCRDC, Frederick, Maryland 21702 [H. F., E. G., R. H. W.], and Biological Carcinogenesis and Development Program, PRI/DynCorp., Frederick, Maryland 21702-1201 [R. L. H., T. T. B., R. B.]

Flavone acetic acid (FAA) is an investigational drug that augments natural killer activity, induces the genes for - and -interferon (IFN) and tumor necrosis factor , and synergizes with recombinant interleukin 2 for the successful treatment of murine renal cancer. However, in most clinical studies of FAA only minimal immunomodulatory effects have been reported. Most of the patients in these studies have also been given sodium bicarbonate to prevent possible nephrotoxicity. The current study was performed to determine whether alkalinization had any effects on FAA-induced immune modulation and therapeutic activity in mice. The results showed that alkalinization inhibited the treatment of murine renal cancer by FAA plus recombinant interleukin 2 such that the survival rate of 84% in nonalkalinized mice was reduced to 0 in mice that were alkalinized during treatment. Alkalinization also significantly inhibited the ability of FAA to augment both splenic and hepatic natural killer activity in a dose-dependent manner. In contrast, alkalinization did not inhibit the ability of polyinosinic:polycytidylic acid and poly-L-lysine stabilized in carboxymethyl cellulose, maleic anhydride divinyl ether, or Propionibacterium acnes to augment liver-associated natural killer activity. By Northern blot analysis, it was shown that the induction of mRNA for IFN-, IFN-, and tumor necrosis factor by FAA in the spleen cells of mice was significantly reduced in alkalinized mice. Consistent with a reduction in the FAA-induced expression of the cytokine genes, alkalinization also resulted in a significant decrease in both the peak serum concentration and duration of detectable IFN activity following FAA treatment. Increasing the dose of FAA in alkalinized mice to 300 mg/kg overcame the deleterious effects of alkalinization for treatment of murine renal cancer by FAA plus recombinant interleukin 2. These results demonstrate that the process of alkalinization inhibits the immunomodulatory and immunotherapeutic effects of FAA in mice and suggest that alkalinization might have similar deleterious effects on FAA-induced immune stimulation in human clinical trials.

¹ This project was funded in part with federal funds from the Department of Health and Human Services, under Contract N01-CO-74102 with Program Resources, Inc./DynCorp.

² Supported during the performance of these studies by a Japanese Overseas Cancer Fellowship from the Foundation for the Promotion of Cancer Research. Current Address: Growth Factor Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan.

³ To whom requests for reprints should be addressed.

Received 6/26/90. Accepted 9/14/90.