Tamoxifen potentiates in vivo antitumor activity of interleukin-2.
Tamoxifen, an antiestrogen with efficacy in treatment of both estrogen receptor-positive and negative breast tumors, may be immunomodulatory. We tested tamoxifen's ability to augment the antitumor activity of interleukin-2 (IL-2), a lymphokine capable of expanding and activating lymphocytes, in the treatment of established pulmonary metastases of the weakly immunogenic murine fibrosarcoma MCA-106. Age-matched C57BL/6 female mice bearing pulmonary metastases induced by a tail vein injection of MCA-106 tumor suspension (5 x 10(5) cells/mouse) were treated from days 3 through 12 with intraperitoneal saline solution or IL-2 (50,000 units twice a day). Half of the mice in each group received plain and the remainder received tamoxifen-treated (2 units/ml) drinking water ad libitum for the duration of the experiment. All mice were killed on day 18 for enumeration of pulmonary metastases. Compared with saline-treated control mice, IL-2 and tamoxifen reduced metastases by 66% (p less than 0.0002) and 30% (p less than 0.005), respectively. IL-2 and tamoxifen combined reduced metastases 95% (p less than 0.0002), significantly better than did IL-2 (p less than 0.02) or tamoxifen (p less than 0.0003) alone. In vitro, tamoxifen inhibited proliferation of the weakly estrogen receptor-positive MCA-106 tumor by approximately 30%. Tamoxifen had no effect on the generation of 3-day IL-2-activated lymphocyte cytotoxicity against both natural killer-sensitive (YAC) and natural killer-resistant (MCA-106) target cells. Both YAC and MCA-106 tumor became more resistant to lysis with increased concentration of tamoxifen. This is the first demonstration of in vivo potentiation of IL-2 antitumor activity by tamoxifen and suggests its possible use clinically.
Kim
B
B
Department of Surgery, University of Utah Medical Center, Salt Lake City.
Warnaka
P
P
Konrad
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005354:Fibrosarcoma / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D007376:Interleukin-2 / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000970:Antineoplastic Agents; D007376:Interleukin-2; D013629:Tamoxifen