Combined effects of chemotherapy and interleukin 2 in the therapy of mice with advanced pulmonary tumors.
We have evaluated the effects of chemotherapeutic agents on the toxicity and antitumor benefit of therapy of established murine tumors by high-dose interleukin 2 (IL-2). Cyclophosphamide (Cy), doxorubicin, and bischloroethylnitrosourea were given to normal mice prior to IL-2 administration to test the effects of these agents on IL-2-induced toxicity. Cy at doses of 100 mg/kg and 150 mg/kg completely protected mice from a 100% lethal dose of IL-2, and doses of 50 mg/kg and 150 mg/kg allowed the administration of a median of 4.5 and 10.0 more doses of IL-2, respectively, before death from IL-2 toxicity occurred. Doxorubicin at 8 mg/kg and bischloroethylnitrosourea at 20 mg/kg did not impact on toxicity in IL-2-treated mice. In mice bearing pulmonary metastases of the weakly immunogenic MCA-105 sarcoma, IL-2 increased median survival time from 33 (no IL-2) to greater than 60 days for all doses of IL-2 tested when combined with a single injection of Cy at 75 mg/kg (P less than 0.002). Increasing doses of either Cy or IL-2 produced increasing benefits on survival which were always greater than either treatment alone. These effects of Cy and IL-2 were also seen in mice bearing the nonimmunogenic MCA-101 sarcoma and a murine adenocarcinoma (MCA-38). Doxorubicin and bischloroethylnitrosourea did not consistently enhance the effects of IL-2 treatment. Cy appears to reduce the yield of in vivo generated lymphokine-activated killer cells, but these lymphokine-activated killer cells are still lytic for fresh tumor targets in vitro. Thus, the mechanism of this synergy does not appear to involve stimulation of lymphokine-activated killer cell activity, but may in part involve reduction of tumor burden by the chemotherapeutic agent, an increase in susceptibility of tumor to cellular immune lysis, and/or a decrease in suppressor cell activity mediated by the chemotherapy.
Papa
M Z
MZ
Surgery Branch, National Cancer Institute, Bethesda, Maryland 20892.
Yang
J C
JC
Vetto
J T
JT
Shiloni
E
E
Eisenthal
A
A
Rosenberg
S A
SA
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000633:toxicity; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008175:Lung Neoplasms / Q000188:drug therapy*; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL
D007376:Interleukin-2; D003520:Cyclophosphamide