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Susceptibility of Chemoresistant Murine and Human Tumor Cells to Lysis by Interleukin 2-activated Lymphocytes¹

Division of Experimental Oncology D [C. G-P., L. R., Mo. R., Ma. R., G. F., G. P.] and B [R. S.], Istituto Nazionale Tumori, Milano, Italy

The sensitivity of three different human and murine doxorubicin (Dx)-sensitive or -resistant pairs of tumor cells to recombinant interleukin 2 (rIL2)-activated lymphocytes was studied. In two pairs of these sublines (LoVo human colon carcinoma and B16 mouse melanoma sublines), resistance to Dx was induced in vitro, while in the third pair (9229 human metastatic melanoma clones), Dx resistance was spontaneously present in clone 9229.24. Dx-resistant cells were efficiently lysed by rIL2-activated lymphocytes in a short-term ⁵¹Cr release assay; in some experiments a trend toward higher lysis of Dx-resistant cells was present. We then tested the tumor cell growth-inhibitory activity of rIL2-activated lymphocytes in the human tumor clonogenic assay after lymphocyte-tumor coculture. Complete inhibition of tumor cell growth was obtained with five of six sublines or clones (both Dx sensitive and resistant) after 3 to 6 days of coculture at effector lymphocyte/target tumor cell ratios of 5 to 50/1; a maximum 99% inhibition was observed with the melanoma clone 9229.4 even after coculture for 6 days at an effector lymphocyte/target tumor cell ratio of 50/1. By using lower effector lymphocyte/target tumor cell coculture ratios (1, 5, 25/1), it was shown that all the three Dx-resistant cell types were significantly more affected by activated lymphocytes than their Dx-sensitive counterparts. The LoVo/DX subline was also more lysed than its Dx-sensitive counterpart LoVo/H subline by an antitumor monoclonal antibody in a complement-mediated cytotoxicity assay, despite the fact that both sublines expressed a similar amount of antigen on the cell surface. These data indicate that Dx-resistant cancer cells are more susceptible to the lysis by rIL2-activated lymphocytes than their Dx-sensitive counterparts and that a complete inhibition of their clonogenic potential can be obtained in vitro.

¹ This work was partially supported by the finalized project "Oncology" of the C. N. R. (Rome, Grant 86.00696.44) and by "Associazione italiana per la ricerca contro il Cancro" of Milan, Italy.

² To whom requests for reprints should be addressed, at Division of Experimental Oncology D, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy.

Received 8/19/87. Revised 11/11/87. Revised 1/15/88. Accepted 1/26/88.

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