To investigate these issues, a mammary adenocarcinoma cell line (MADB106), syngeneic to the inbred Fischer 344 rats studied, was used. After intravenous (i.v.) injection, MADB106 cells seed and colonize only in the lungs, a process that has been shown to be controlled by NK cells. Specifically, NK cell control is exerted in a time dependent and decremental manner only during the first 24 hours after i.v. injection. The lung retention of radiolabeled MADB106 cells at 16 hours after injection is highly associated with the number of tumor colonies that would be evident in the lungs 3 weeks later and is a useful indicator of in vivo NK activity.

       In normal rats, females exhibit less resistance against MADB106 tumor cell retention and less NK cytotoxic activity compared to males, and diestrus females fare better than proestrus/estrus females in both outcomes. Although the size of this sex/estrous effect is comparatively small, it perseveres through the more than twofold effects of surgery-induced increases in metastasis, such that proestrus/estrus females undergoing surgery exhibited significantly greater lung retention of MADB106 cells compared to diestrus surgery females. Surgery resulted in the suppression of NK cytotoxic activity assessed in vitro; however, sex and estrous phase differences were not apparent.

       To assess the possible benefits of providing pain-relieving medication on surgery-induced decreases in host resistance against the lung retention of MADB106 cells, males and females were used in a simple 2x2 experimental design (surgery with anesthesia vs anesthesia alone and drug vs vehicle). Surgery and the provision of pre- and postoperative fentanyl resulted in a significant interaction such that fentanyl attenuated the surgery-induced increase in tumor cell retention observed in both male and female animals. In vitro NK cytotoxicity studies revealed only surgery-induced NK suppression; fentanyl exerted no effects. These findings are consistent with our previous work using morphine treatment. In particular, although both opiates were shown to enhance host resistance against surgery-induced increases in the retention of NK-sensitive tumor cells, in vitro findings yielded either no effect (fentanyl) or were NK-suppressive (morphine). Early work using the nonsteroidal anti-inflammatory drug indomethacin indicates possible sex differences in its beneficial effects on the tumor-enhancing consequences of surgery. Specifically, whereas indomethacin treatment ameliorates surgery-induced increases in tumor cell retention in females, the males derived no benefit from this intervention.