asialo-gm1-ganglioside and flavone-acetic-acid

Flavone acetic acid (FAA) is one of the most active antitumour agents against mouse solid tumours. A number of reports favour the hypothesis that FAA could behave as a biological response modifier; in fact FAA stimulates natural killer (NK) cells, induces secretion of type I interferon and synergizes with interleukin-2 to increase NK/lymphokine-activated killer (LAK) activity in vivo. However, there is no conclusive evidence that the antitumour activity of FAA is mediated via the modulation of NK/LAK cells. The present study was designed to evaluate whether the reported activation of NK cells is instrumental in FAA antitumour activity. FAA (180 mg/kg, i.v. on days 3, 7 and 11 after tumour implant) was significantly effective in inhibiting the subcutaneous growth of the pancreatic adenocarcinoma PAN/03 in C57/Bl mice. After 132 days the number of tumour-free survivors was 36%, whereas in the control group receiving no treatment, or in the group of mice treated with 10 micrograms/mouse of alpha-asialo-GM1 the value was only 0 or 6.7%, respectively. The combination of FAA and alpha-asialo-GM1 resulted in only 6% tumour-free mice. In parallel experiments, splenocytes and peritoneal cells from C57/B1 mice were tested in a standard cytotoxicity NK assay. While animals treated with FAA showed a significant increase in NK activity, those injected with alpha-asialo-GM1 had very low levels, and the combined treatment of FAA and alpha-asialo-GM1 resulted in a lower or similar NK activity compared to that in untreated mice. The fact that the abrogation of the NK-stimulating effect of FAA is accompanied by a lack of anti-tumour activity indicates that, at least in this experimental model, FAA is likely to act via an immunomodulatory mechanism.

Topics: Adenocarcinoma; Animals; Flavonoids; G(M1) Ganglioside; Glycosphingolipids; Immunity, Cellular; Immunity, Innate; Killer Cells, Natural; Mice; Mice, Inbred C57BL; Pancreatic Neoplasms

The investigational drug flavone-8-acetic acid (FAA) potently augments NK activity in the spleen, liver, lungs, and peritoneum in a dose-dependent manner after i.v. or i.p. administration. Augmented NK activity peaks by 24 h after FAA injection and returns to normal after 6 days. Combined treatment of established murine renal cancer with FAA and rIL-2 results in up to 80% long term survival whereas FAA or rIL-2 alone were unable to induce any long term survivors. The optimal dose of rIL-2 required for use with FAA was in the range of 10,000 to 30,000 U/day. Further studies demonstrated that the regimen of FAA plus rIL-2 administration that was effective in treating established murine renal cancer also induced a more potent augmentation of NK activity than did either FAA or rIL-2 alone. Subsequent studies revealed that the therapeutic effectiveness of FAA plus rIL-2 was significantly reduced when tumor-bearing mice were treated with anti-asialo GM1 serum. These results are consistent with a role for augmented NK activity in the therapeutic effects of FAA plus rIL-2 murine renal cancer. In addition, these studies demonstrate that FAA and rIL-2 is a useful approach for cancer treatment in that subtoxic doses of rIL-2 can be used and significant anti-tumor efficacy occurs even without accompanying adoptive immunotherapy.

Topics: Animals; Antineoplastic Agents; Cytotoxicity, Immunologic; Drug Synergism; Flavonoids; G(M1) Ganglioside; Glycosphingolipids; Immunity, Innate; Immunotherapy; Interleukin-2; Kidney Neoplasms; Killer Cells, Natural; Mice