Correlation between the sensitivity or resistance to IL‐2 and the response to cyclophosphamide of 4 tumors transplantable in the same murine host

Greco, Giampaolo; Gabriele, Lucia; Rozera, Carmela; Venditti, Massimo; Belardelli, Filippo; Proietti, Enrico

doi:10.1002/ijc.2910620213

Cited by 2 publications

(3 citation statements)

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“…1 shows the effects of a single injection of CTX, followed 5 h later by one injection of 10 8 immune spleen cells, on tumor growth and survival time in mice bearing 4-d tumors obtained after sub-cutaneous injection of either 3Cl-8 FLC or ESb cells. Confirming previous findings (32), CTX alone induced some inhibition of tumor growth in both these tumor models, although all the treated mice died from visceral metastases. Inoculation of immune spleen cells alone did not significantly affect the growth of FLC or ESb tumors.…”

Section: Resultssupporting

confidence: 91%

“…veloped after the injection of Eb or p11-R-Eb lymphoma cells. In these tumor models, we had previously failed to observe any therapeutic response to CTX alone, while the tumorinjected mice proved highly responsive to IL-2 therapy (32). Under the experimental conditions used in the experiments illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In an attempt to determine the possible mechanisms responsible for such a powerful antitumor response, studies were performed using 3Cl-8 FLC line because of the extensive information available on the in vivo behavior of these tumor cells and their response to different therapy regimens. This highly metastatic tumor has been used widely by our group for evaluating the antitumor response to type I IFN (44)(45)(46)(47) and other cytokines, as well as to chemotherapy (32,(48)(49)(50). In particular, DBA/2 mice bearing metastatic FLC do not develop a clear antitumor response after treatment with various cytokines or chemotherapeutic agents, with the notable exception of type I IFN, which markedly inhibited tumor growth and visceral metastases (41,48).…”

Section: Resultsmentioning

confidence: 99%

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Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice.

Proietti¹,

Greco²,

Garrone³

et al. 1998

J. Clin. Invest.

144

145

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Cyclophosphamide (CTX) increases the antitumor effectiveness of adoptive immunotherapy in mice, and combined immunotherapy regimens are now used in some clinical trials. However, the mechanisms underlying the synergistic antitumor responses are still unclear. The purpose of this study was (a) to evaluate the antitumor response to CTX and adoptive immunotherapy in mice bearing four different syngeneic tumors (two responsive in vivo to CTX and two resistant); and (b) to define the mechanism(s) of the CTX-immunotherapy synergism. Tumor-bearing DBA/2 mice were treated with a single injection of CTX followed by an intravenous infusion of tumor-immune spleen cells. In all the four tumor models, a single CTX injection resulted in an impressive antitumor response to the subsequent injection of spleen cells from mice immunized with homologous tumor cells independently of the in vivo response to CTX alone. Detailed analysis of the antitumor mechanisms in mice transplanted with metastatic Friend leukemia cells revealed that (a) the effectiveness of this combined therapy was dependent neither on the CTX-induced reduction of tumor burden nor on CTX-induced inhibition of some putative tumor-induced suppressor cells; (b) the CTX/immune cells' regimen strongly protected the mice from subsequent injection of FLC, provided the animals were also preinoculated with inactivated homologous tumor together with the immune spleen cells; (c) CD4(+) T immune lymphocytes were the major cell type responsible for the antitumor activity; (d) the combined therapy was ineffective in mice treated with antiasialo-GM1 or anti-IFN-alpha/beta antibodies; (e) spleen and/ or bone marrow cells from CTX-treated mice produced soluble factors that assisted in proliferation of the spleen cells. Altogether, these results indicate that CTX acts via bystander effects, possibly through production of T cell growth factors occurring during the rebound events after drug administration, which may sustain the proliferation, survival, and activity of the transferred immune T lymphocytes. Thus, our findings indicate the need for reappraisal of the mechanisms underlying the synergistic effects of CTX and adoptive immunotherapy, and may provide new insights into the definition of new and more effective strategies with chemotherapy and adoptive immunotherapy for cancer patients.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%