THF-γ2, a thymic hormone, increases immunocompetence and survival in 5-fluorouracil-treated mice bearing MOPC-315 plasmacytoma

We studied the effect of combined chemo-immunotherapy, 5-FU followed by thymosin alpha 1 (T alpha 1) and interleukin-2 (IL-2) at low doses, on liver metastases from colorectal cancer, induced by splenic injection of DHD/K12 cells (1,2-dimethylhydrazine-induced colon adenocarcinoma) in syngeneic BDIX rats. The presence of liver metastases was checked by laparotomy 14 days after tumor-cell injection. Evaluable rats were assigned randomly to 5 experimental groups designated as control, 5-FU, IL-2, 5-FU/IL-2 and 5-FU/T alpha 1/IL-2. 5-FU was administered i.v. as a continuous infusion for 7 days by an osmotic device implanted surgically. T alpha 1 and IL-2 were administered for 4 days and repeated after 11 days. Combined chemo-immunotherapy was shown both to significantly reduce the growth of liver metastases and to prevent extra-hepatic spread. 5-FU/T alpha 1/IL-2 also improved survival rate. Combined immunotherapy after 5-FU restored NK activity of the peripheral-blood-mononuclear-cell (PBMC) in tumor and/or 5-FU immunodepressed rats and enhanced PBMC cytotoxic activity against the DHD/K12 autologous cell line. This model was devised to mimic the clinical situation of unresectable liver metastases.

mentioning

confidence: 99%

Anti‐tumor effect of combined treatment with thymosin alpha 1 and interleukin‐2 after 5‐fluorouracil in liver metastases from colorectal cancer in rats

Rasi¹,

Silecchia

Vallebona

et al. 1994

“…Administration of THF-y2 increases immune competence in 5-FU-treated mice bearing MOPC-3 15 plasmacytoma (Ophir et al, 1989) and repairs the immunodeficiency of mice cured of MOPC-315 plasmacytoma by melphalan (Ophir et al, 1990). We now show the potential of a megadose of THF-y2 to improve the effectiveness of therapy when used in combination with immunosuppressive anticancer drugs.…”

Section: Discussionmentioning

confidence: 84%

“…Accordingly, it is conceivable that additional treatment with a T-cell modulator such as THF-y2 may improve the effectiveness of chemotherapy with alkylating drugs, under conditions in which chemotherapy alone is only partially effective. Such conditions administration (Ophir et al, 1989) prolonged the survival time of MOPC-315 TB mice. Either low doses of THF-y2 alone (Ophir et al, 1989), or megadoses of THF-y2 alone (data not shown), had no effect on survival time of mice bearing MOPC-3 15 tumors.…”

Section: Discussionmentioning

confidence: 96%

“…Such conditions administration (Ophir et al, 1989) prolonged the survival time of MOPC-315 TB mice. Either low doses of THF-y2 alone (Ophir et al, 1989), or megadoses of THF-y2 alone (data not shown), had no effect on survival time of mice bearing MOPC-3 15 tumors. In the present work, we tried to determine whether a considerable increase in the dose of THF-y2 injected ("mega" dose) augments the therapeutic effectiveness in combination with either L-PAM or 5-FU.…”

Section: Discussionmentioning

confidence: 96%

“…We have previously shown (Ophir et al, 1989) that 8 daily injections of a low dose of THF-y2 increased the survival time of MOPC-315 TB mice treated with 5-FU (200 mg/kg). In the present experiments we aimed to determine whether prolonged administration of low doses of THF-y2 would increase its therapeutic efficacy in combination with 5-FU.…”

Section: Effect Of Combined 5-fu and Thf-y2 Therapymentioning

confidence: 97%

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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

Ophir

Pecht

Burstein

et al. 1991

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.

A synthetic thymic hormone, THF‐γ2, repairs immunodeficiency of mice cured of plasmacytoma by melphalan

Ophir

Pecht

Rashid

et al. 1990

BALB/c mice cured of large MOPC-315 plasmacytomas by melphalan remain deficient in their spleen T-cell functions. This was manifested by impairment of the allogeneic and the antibody responses in vitro to SRBC and in decreased numbers of T-cells including their subsets CD4 and CD8. IL-2 production and specific cytotoxicity against MOPC-315 tumor cells were, on the other hand, maintained. Treatment of these cured mice by in-vivo administration of THF-gamma 2, an octapeptide from calf thymus, repaired these deficits. This was evidenced by in vitro tests with spleen cells which manifested an increased allogeneic response and elevated generation of primary antibody response, restoration of T-cell subpopulations to normal and an enhanced IL-2 production above normal levels. The potential use of THF-gamma 2 as supportive therapy in cancer treatment is suggested.