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The therapeutic effects of tryptanthrin (TRYP), a natural product from the medicinal plant Polygonum tinctorium, were examined in a murine model of inflammatory bowel disease (IBD). Colitis was induced by 5% dextran sodium sulfate (DSS) in drinking water for 7 days from day 0. TRYP (100 mg/kg) was administered orally suspended in 5% arabia gum everyday from day 3 for 5 days. Histopathological analysis showed reduced colon damage in TRYP-treated mice on day 6; however, colon injury resumed after treatment was stopped. The production of prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) by untreated and treated mouse colon tissues cultured in vitro were mostly unchanged by TRYP treatment. However, mitogen-stimulated spleen cells from TRYP-treated colitic mice produced less interleukin 2 (IL-2) and less interferon-gamma (IFN-gamma) than untreated colitic mouse spleen cells, early after induction of colitis. When colitis was induced with 5% DSS for 7 days and TRYP was given to the mice for 8 days from day 3, TRYP enhanced the survival of the mice but results were not significant. A significant reduction of weight loss was observed in TRYP-treated mice with colitis induced by 5% DSS for 4 days as compared to control mice. Remarkably, whereas 90% of the vehicle-treated mice died from wasting disease, all the TRYP-treated mice survived, suggesting that TRYP may have a therapeutic effect on colitis.

Human melanoma Colo 679 cells were made resistant to doxorubicin (adriamycin, ADM) by continuous exposure to ascending concentrations of the drug and Colo/ADM80; a variant which grew continuously in the presence of 80 ng/ml of ADM was thus established. Human peripheral blood mononuclear cells (PBMC) produced interferon gamma (IFN-gamma) when cultured with mitomycin C (MMC)-treated parental Colo 679 cells. The synthesis of IFN-gamma was synergistically enhanced by adding interleukin-18 (IL-18) and this was IL-12-dependent because a neutralizing antibody against IL-12 almost completely inhibited IFN-gamma production while control antibodies (Abs) were inactive. The cellular sources of IFN-gamma were found to be B cells, CD8+ T cells and CD4+ T cells as revealed by flow cytometry after double staining for surface antigens and staining for intracellular IFN-gamma. Interestingly, the resistant cell line induced much less IFN-gamma production than the parental cell line under the same co-culture conditions; however, IL-18 could still enhance the production of IFN-gamma. In conclusion, our study shows that acquired resistance to anti-cancer agents can also reduce immune responses to cancer cells. However, the immunostimulatory cytokine IL-18 could still enhance IFN-gamma production in drug resistant tumor cell-PBMC cultures indicating that such immunostimulatory agents could still be beneficial in immunotherapy for patients with recurrent drug resistant tumors.