CYTOKINE INDUCTION AND THERAPEUTIC SYNERGY WITH INTERLEUKIN-2 AGAINST MURINE RENAL AND COLON CANCERS BY XANTHENONE-4-ACETIC ACID-DERIVATIVES

Derivatives of xanthenone-4-acetic acid (XAA) have been found to have similar activity to flavone-8-acetic acid against transplantable solid tumors. Some of these compounds were compared to flavone acetic acid (FAA) in their ability to induce cytokines as well as to mediate antitumor effects against murine renal cancer (Renca) and a mouse colon cancer (MCA-38). 5-Methyl-XAA and 5-chloro-XAA proved to be more potent than FAA on a mg/kg basis for induction of the genes for IFNalpha, IFNgamma, and TNFalpha, and for IFN and TNF activities in the sera of treated mice. These effects were sharply dose dependent. On the other hand, 7-methyl-XAA, which has no antitumor activity, did not induce these genes. In addition, 5-methyl-XAA and 5-chloro-XAA but not 7-methyl-XAA synergized with recombinant human interleukin-2 (rhIL-2) for the treatment of Renca and MCA-38. Doses of the active derivatives that failed to induce cytokines also exhibited no therapeutic synergy with rhIL-2. These results suggest that at least some of the antitumor effects of these XAA derivatives are related to their ability to induce cytokines.