Interferon and interferon inducers in the treatment of cancer : experimental studies in mice, rats and humans
Interferon en interferon inducers in de behandeling van kanker : experimentele studies in muizen, ratten en mensen
Biological response modifiers are agents that · exert their antitumor effects mainly or exclusively through modulation of host immune defense mechanisms. A common feature of these agents is their capacity to induce the production of endogenous interferons and/ or other lymphokines in vivo, and their capacity to activate various subsets of lymphocytes and monocytes that can lyse tumor cells in vitro and in vivo. Antiproliferative and immunomodulative effects as well as toxicity and side-effects observed in connection with the administration of these agents may differ greatly. Relatively recently the 6-aryl pyrimidinones, a series of small molecule biological response modifiers, were discovered. It was found that these agents varied greatly with respect to antiviral, antiproliferative and immunomodulative activity as well as with respect to the toxic side-effects. Because of its effective induction of endogenous interferon, its significant immunostimulatory effects on NK cells and its low toxicity, ABPP (2-amino-5-bromo-6-phenyl-4-(3H)-pyrimidinone) appeared to be one of the most interesting and promising pyrimidinones. Most of the initial literature concerning the biological effects of ABPP dealt with NK-cell activity, assessed in vitro by 51chromium release cytotoxicity assays with NK-cell sensitive target cells, and in vivo anti tumor activity against non-established tumor (tumor cells in the blood born or early lodging phase) . Both assessments of potential anti tumor efficacy should be interpreted with great caution. It is known that most cultured tumor cell-lines are NI<-sensitive and that in vitro cytotoxic activity may correspond poorly with in vivo antitumor effects, whereas fresh tumor cell preparations are usually NK-resistant and the capacity of activated killer cells to lyse these targets (LAK cell activity) corresponds well with antitumor activity of these cells in vivo. The evaluation of in vivo antitumor effects should not be based on results obtained with "non-established" (day 0-1 after inoculation of the tumor) metastatic tumor only. Established metastatic tumor (day 3 or later after inoculation of the tumor) is quite resistant to NK-cell mediated killing and corresponds much better with the relevant clinical situation where an effective adjuvant treatment regimen in the presence of micrometastases at the time of removal of the primary tumor determines the ultimate outcome of treatment. Because of the arguments presented above we studied (A) the capacity of ABPP to generate LAK cel,l activity in vivo; (B) the importance of tumor load (nonestablished, early established and advanced tumor) and tumor site on the outcome of treatment with ABPP; (C) ways to augment immunotherapeutic effects with ABPP by combining ABPP with: other biologicals (Interferon-gamma, Interleukin- 2, Tumor Necrosis Factor) and with (D) cyclophosphamide in a search for treatment schedules ,that may hold promise in an adjuvant setting.
|Keywords||interferon, treatment, cancer, mice, rat, human, necrosis|
|Promotor||J. Jeekel (Hans)|
|Publisher||Erasmus University Rotterdam|
Eggermont, A.M.M. (1987, October). Interferon and interferon inducers in the treatment of cancer : experimental studies in mice, rats and humans. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/51226