Tumoricidal and immunomodulatory activities of drugs and implications for therapy of mice bearing a late stage MOPC-315 plasmacytoma

Berko, Retford; Seissman, Katherine; Colvin, Michael; Bocian, Robert C.; Ben-Efraim, Shlomo; Dray, Sheldon

doi:10.1016/0192-0561(88)90006-9

Cited by 7 publications

(7 citation statements)

References 12 publications

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“…The mechanism of lymphopenia‐induced regeneration is not clear. A possible immunomodulatory effect of cytotoxic drugs has been described for various chemotherapeutic agents 20–24. Interleukin‐7 and dendritic cell derived interleukin‐15 have been reported to stimulate both T cell regeneration and T cell function 25–29 and are believed to play an essential role in homeostasis driven repopulation.…”

Section: Discussionmentioning

confidence: 99%

Enhanced lymphocyte proliferation responses in pediatric patients early after myelosuppressive chemotherapy

Stachel

Fütterer²,

Haas³

et al. 2004

Pediatric Blood & Cancer

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Section: Discussionmentioning

confidence: 99%

Enhanced lymphocyte proliferation responses in pediatric patients early after myelosuppressive chemotherapy

Stachel

Fütterer²,

Haas³

et al. 2004

Pediatric Blood & Cancer

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“…DISCUSSION Previous studies (Ben-Efraim et al, 1983;Dray and Mokyr, 1989) have shown that mice bearing MOPC-315 tumors have the ability to develop a host-specific anti-tumor immune response. The development of such a response was facilitated by chemotherapy with alkylating drugs such as cyclophosphamide (Hengst et al, 1980), melphalan (Ben-Efraim et al, 1983;Bocian et al, 1984) and BCNU (Berko et al, 1988). The mechanism of facilitation of host anti-tumor immune response by alkylating drugs is not fully understood.…”

Section: Effect Of Combined L-pam and Thf-y2 Therapymentioning

confidence: 99%

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

Intl Journal of Cancer

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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.

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“…mediated by such effectors. A maximum of 15% specific lysis DISCUSSION BCNU is an anti-tumor agent found to be very effective against a range of experimental tumors (Berko et al, 1988;Carter et al, 1972;Feola and Mmyama, 1979;KaDlan. 1985: Schabel.…”

Section: Bcnu Balb/c Anti-yca Donorsmentioning

confidence: 99%

“…The effectiveness of several anti-cancer agents can be highly dependent on the contribution of host anti-tumor immunity. This has been documented for the alkylating drugs 1,3bis(2-chloroethy1)-1-nitrosourea (BCNU), cyclophosphamide (CY) and L-phenylalanine mustard (L-PAM), all of which cause a high percentage of cures in mice bearing different neoplasms (Awwad and North, 1989;Ben-Efraim et al, 1983;Berko et al, 1988;Feola and Maruyama, 1979;Dray, 1983, Mokyr, 1987;Kaplan, 1985, Nagarkatti et al, 1988b). The outcome of chemotherapy for such tumor bearers was indeed attributed to the immunomodulatory activity of these antineoplastic agents which allow a potent Tcell-dependent anti-tumor immunity to appear.…”

mentioning

confidence: 96%

Eradication of a disseminated mouse lymphoma by 1,3‐BIS(2‐chloroethyl)‐1‐nitrosourea is immunologically mediated and accompanied by de novo generation of anti‐tumor cytotoxicity

Sensi

Bergomi

Formelli

et al. 1990

Intl Journal of Cancer

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The anti-tumor effect of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was examined in BALB/c mice bearing increasing burdens of a syngeneic lymphoma (YC8). A single i.p. injection of the drug resulted in over 75% of cures when given at day 3, 5, 7 or 10 after an i.v. inoculum of 10(4) YC8 cells. The efficacy of BCNU on mice bearing large tumor burdens (from day 5 on) was not only due to its tumoricidal activity, but was immunologically mediated. Residual tumorigenic cells could be recovered in the livers of 5-day tumor bearers (TB) up to 2 weeks after BCNU treatment and only a low percentage of cures could be achieved when BCNU was administered to nude mice. In addition, BCNU-cured mice specifically rejected a lethal YC8 challenge and their splenocytes developed anti-tumor cytotoxicity in response to in vitro stimulation with YC8 cells. During kinetic experiments a 2-week period elapsed after BCNU injection before an anti-tumor cytotoxic T-lymphocyte (CTL) response could be generated by spleen cells of BCNU-treated 5-day TB. This period was characterized by immunosuppression as evaluated from impairment in the generation of lymphokine-activated killer (LAK) cells or of allospecific primary CTL responses by spleen cells from BCNU-treated 5-day TB and BCNU-treated normal mice. LAK cells first recovered and could be generated 7 days later, whereas primary allospecific CTL responses could only be detected by day 14, concomitantly with the generation of anti-tumor cytotoxicity by 5-day TB. The development of secondary in vitro CTL responses, however, was permanently abrogated. Spleen cells from BALB/c mice immunized either with YC8 or with DBA/2 minor histocompatibility antigens and treated with BCNU 1 week after the last immunization failed to mount an in vitro CTL response to their immunizing antigen, even when the cultures were supplemented with recombinant interleukin-2.

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Tumoricidal and immunomodulatory activities of drugs and implications for therapy of mice bearing a late stage MOPC-315 plasmacytoma

Cited by 7 publications

References 12 publications

Enhanced lymphocyte proliferation responses in pediatric patients early after myelosuppressive chemotherapy

Enhanced lymphocyte proliferation responses in pediatric patients early after myelosuppressive chemotherapy

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

Eradication of a disseminated mouse lymphoma by 1,3‐BIS(2‐chloroethyl)‐1‐nitrosourea is immunologically mediated and accompanied by de novo generation of anti‐tumor cytotoxicity

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