IFN-beta partially counteracts inhibition of natural killer activity induced by some antitumor agents.
We investigated whether recombinant human (rHu-IFN-beta) (IFN-beta) could counteract the inhibition of natural killer (NK) activity caused by antitumor agents. Peripheral blood lymphocytes (PBL) were incubated with different antitumor agents alone or in combination with IFN-beta for 3 days and then tested in a cytotoxicity assay against the K562 cell line. The following drugs were used, all of which caused a dose-dependent inhibition of NK activity: etoposide, camptothecin, doxorubicin, cis-DDP, tallimustine, and L-PAM. Concomitant treatment with (1000 U/ml) IFN-beta counteracted the inhibitory effect of etoposide and camptothecin but had no consistent effect on the inhibition mediated by the other drugs. Mean values of inhibition of NK activity at 1 microM camptothecin was 48%+/-3.4% and with IFN-beta was 10%+/-4.9%. With 100 microM etoposide, mean value of inhibition was 78%+/-3.3%, and with IFN-beta, it was 18%+/-1.5%. Cell viability, assessed by vital dye exclusion, and drug uptake, assessed with radiolabeled etoposide, were similar in cells treated with or without IFN-beta. The protective effect of IFN-beta on NK function was rather selective, as IFN-beta did not counteract the drug-mediated inhibition of PBL proliferation when stimulated by phytohemagglutinin (PHA). Other cytokines, IFN-alpha, IFN-gamma, and interleukin-2 (IL-2), had similar protective effect, although IFN-beta, was slightly more potent. On the other hand, IL-6, a cytokine sharing some properties with IFNs was ineffective. Camptothecin inhibited the expression of mRNA for granzyme B, a lytic protein involved in lymphoid-mediated cytotoxicity. Combined treatment with IFN-beta restored-at least in part-the transcription of granzyme B mRNA. These results show that the immunosuppressive effect of some antitumor agents could be partly counteracted by treatment with IFN-beta.
Allavena
P
P
Department of Immunology and Cell Biology, Istituto Mario Negri, Milano, Italy.
Giardina
G
G
Sen
S
S
Colella
G
G
Broggini
M
M
D'Incalci
M
M
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002166:Camptothecin / Q000037:antagonists & inhibitors*; D002945:Cisplatin / Q000627:therapeutic use; D003601:Cytotoxicity Tests, Immunologic; D004214:Distamycins / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005047:Etoposide / Q000037:antagonists & inhibitors*; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors*; D016899:Interferon-beta / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008558:Melphalan / Q000627:therapeutic use; D009588:Nitrogen Mustard Compounds / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004214:Distamycins; D007166:Immunosuppressive Agents; D009588:Nitrogen Mustard Compounds; D011994:Recombinant Proteins; D005047:Etoposide; C066900:tallimustine; D016899:Interferon-beta; D004317:Doxorubicin; D002945:Cisplatin; D008558:Melphalan; D002166:Camptothecin