Flavone acetic acid (FAA) is an
investigational drug that augments natural killer activity, induces the genes for alpha- and
gamma-interferon (IFN) and
tumor necrosis factor alpha, 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-alpha, IFN-gamma, and
tumor necrosis factor alpha 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.