Susceptibility of human and murine drug-resistant tumor cells to the lytic activity of rIL2-activated lymphocytes (LAK).
This article surveys the available data on the sensitivity of drug-resistant tumor cells to recombinant interleukin 2 (rIL2)-activated lymphocytes (LAK). In our own study, three different experimental systems were used: 1. in vitro treatment of tumor cells with an anticancer drug followed by the use of surviving cells as targets of LAK; 2. use of pairs of drug-resistant and drug-sensitive cell sublines; 3. analysis of several tumor clones obtained from the same tumor. The antitumor activity of LAK was evaluated both by the 51Cr release and the human tumor clonogenic assay (HTCA). In all the experimental systems used, drug-resistant tumor cells were found to be significantly lysed by LAK, with a consistent trend towards a higher susceptibility than their drug-sensitive counterparts. A positive correlation between the sensitivity to LAK and the ID50 for doxorubicin (Dx) was found in 44 melanoma clones analyzed, suggesting that spontaneously drug-resistant clones have a higher sensitivity to LAK than the drug-sensitive clones. Drug-resistant cells were also more sensitive to antibody and complement-mediated lysis, whereas the higher lysis of drug-resistant tumor cells exerted by LAK was maintained in a lectin dependent cytotoxicity assay. These data offer a rationale for combining chemotherapy with adoptive immunotherapy in the treatment of cancer. Moreover, studying the reasons for the higher LAK sensitivity of drug-resistant tumor cells may provide insights into the mechanisms by which tumor cells can resist LAK action.
Gambacorti-Passerini
C
C
Division of Experimental Oncology D, Istituto Nazionale Tumori, Milano, Italy.
Rivoltini
L
L
Radrizzani
M
M
Supino
R
R
Mariani
M
M
Parmiani
G
G
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D004351:Drug Resistance; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008546:Melanoma, Experimental / Q000628:therapy; D009369:Neoplasms / Q000628:therapy*; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured / Q000187:drug effects
D007376:Interleukin-2; D011994:Recombinant Proteins; C048341:mafosfamide; D003520:Cyclophosphamide