Therapeutic effectiveness against mopc—315 plasmacytoma of low or high doses of the synthetic thymic hormone THF—γ2 in combination with an “immunomodulating” or a “non—immunomodulating” drug

Abstract

We reported previously that treatment of mice bearing MOPC-3 I5 plasmacytoma with the drugs L-PAM (phenylalanine mustard or 5-FU (5-fluorouracil), in combination with survival time than treatment with the drug alone. We show here that in the combined treatment using a single injection of 5-FU followed by multiple (&IS) injections of THF-72, the megadoses were more effective than the low doses in increasing the survival time of MOPC-315 tumor-bearing mice. On the other hand, in combination with L-PAM, both low and high doses of THF-y2 were equally effective. The need for high doses of THF-y2, when used in combination with 5-FU, could be due to the fact that 5-FU acts as a "non-immunomodulating" drug and has to be used at a high, immunosuppressive dose. low doses of 4 HF-72, was more effective in increasing their THF (thymic humoral factor) is an immunologically active soluble fraction which was isolated from dialyzates of calf thymus homogenates (Kook et al., 1975). THF increases Tcell differentiation and immunological competence in animal models in vitro and in vivo (Trainin et al., 1985). THF-y2 has been purified from calf thymus and has been chemically syn- In view of the established properties of THF-y2 in the restoration of immunocompetence, we attempted in the present work to determine whether an increase in the dose of THF-y2 would render chemotherapy with 5-FU more effective. Concomitantly, we determined the effect of low or high doses of THF-y2 in combination with L-PAM. We show here that low and high doses of THF-y2 were equally effective in combination with L-PAM, but the megadose of THF-y2 was more effective than the low dose when administered in combination with a high, immunosuppressive dose of 5-FU. MATERIAL AND METHODS Micethe Tel-Aviv University, Israel, were used. TumorMOPC-3 15 murine plasmacytoma was maintained in vivo by serial S.C. inoculations into syngeneic BALBIc mice. For preparation of tumor-cell suspensions, the tumor was mechanically disrupted in physiological saline solution and cell viability was determined by Trypan blue dye exclusion. Groups of 10-15 mice were inoculated S.C. with 2 X lo5 viable MOPC-315 tumor cells in 0.2 ml. The day of inoculation was considered as day "0" of the experiment. ReagentsMelphalan (L-PAM, Burroughs-Wellcome, Research Triangle Park, NC) was prepared as described by Takesue et al. (1987). A stock solution of 10 mglml was prepared in acid/ alcohol-propylene glycol buffer immediately before use and further diluted in PBS. A quantity of 1 mglkg was i.p. injected. 5-fluorouracil (5-FU:Abic, Ramat-Gan, Israel) was injected i.p. at a dose of 200 mglkg body weight. Synthetic THF-y2, prepared by the solid-phase technique of Merrifield (1963) and purified by reverse-phase HPLC, was used.