Analysis of metastatic spread and growth of tumor cells in mice with depressed natural killer activity by anti-asialo GMl antibody or anticancer agents

Abstract

The mechanism of artificial and spontaneous metastases of tumor was analyzed in B16 melanoma cells and C57BL/6 mice by using anti-asialo GM1 antibody and anticancer agents. Single administrations of 500 micrograms anti-asialo GM1 antibody resulted in significantly decreased NK activity in spleen cells of C57BL/6 mice, lasting 10 days from the day following administration. Treatment with anti-asialo GM1 antibody never decreased the function of T lymphocytes measured by blastogenesis with phytohemagglutinin or T cell growth factor. The tumoricidal functions of activated macrophages but not of resident macrophages were decreased by in vivo treatment with anti-asialo GM1 antibody. The anti-asialo GM1 antibody was evaluated in terms of the enhancing effect on pulmonary metastases with regard to the timing of administration. Treatment with anti-asialo GM1 antibody 1 day before or on the day of tumor inoculation resulted in a substantial increase in the number of artificial pulmonary metastases. In the experimental system of spontaneous metastases, anti-asialo GM1 antibody most effectively increased the number of pulmonary metastases when administered 1-2 weeks before the removal of primary tumor, when the tumor cells are thought to be released into blood circulation from the primary site. In addition, accelerated growth of transplanted tumors at the primary site was observed in mice treated with anti-asialo GM1 antibody. These results strongly suggest that anti-asialo GM1 antibody enhances the incidence of in vivo tumor metastases and the growth of transplanted tumor mainly by suppressing the function of NK cells. The maximum effective dose (MED) of mitomycin C or its derivative (M-83) suppressed NK activity significantly, and pretreatment with these anticancer agents enhanced the growth of the artificial pulmonary and liver metastases. In contrast, the MED of cDDP showed no effect on the NK activity or the numbers of pulmonary and liver metastases. These results indicate that the depression of NK activity induced by chemotherapy results in the promotion of metastatic disease. From these studies it can be concluded that NK cells have a key role in the control of metastases of malignant disease, and that support of NK activity is very important for the prevention of metastases.

Adverse effects of intraportal chemotherapy on natural killer cell activity in colorectal cancer patients

“…NK cells which play an important role in nonspecific immunosurveillance, also inhibit the metastatic process in its early stages [27,28]. Thus it can be postulated that although intraportal chemotherapy is advocated to prevent hepatic metastases, it may also exert an unfavorable influence on immunological activity of the host, which plays an important role in preventing metastases.…”

Role of NOX2-Derived Reactive Oxygen Species in NK Cell–Mediated Control of Murine Melanoma Metastasis

“…Role of NK cells for melanoma metastasis in WT and Nox2-KO mice NK-cell function is reportedly critical to limit lung metastasis in experimental models of murine melanoma (23,28). To define the role of NK cells in the context of NOX2 inhibition, WT and Nox2-KO mice were depleted of NK cells by anti-NK1.1 antibody treatment prior to melanoma cell inoculation.…”

Low-dose Cisplatin-5-Fluorouracil Prevents Postoperative Suppression of Natural Killer Cell Activity in Patients with Gastrointestinal Cancer

“…Lundy et al (26) reported that perioperative immunosuppression could promote the growth of micrometastases. Saijo et al (8) demonstrated that the suppression of NK cell activity by MMC enhanced the growth of experimental pulmonary and liver metastases in mice. Our results suggest that MMC given by bolus injection may be contraindicated as postoperative adjuvant chemotherapy because of its adverse effect on NK cell activity.…”

“…The drug most commonly used in Japan is mitomycin C (MMC) (2); the maximum effective dose of MMC suppresses natural killer (NK) cell activity and pretreatment with Received January 12, 1998; accepted March 23, 1998 For reprints and all correspondence: Koichi Ishikawa, Department of Surgery I, Oita Medical University, 1-1 Idaigaoka, Hasama-machi, Oita 879-5593, Japan Abbreviations: CDDP, cisplatin; 5-FU, 5-fluorouracil; MMC, mitomycin C; NK, natural killer; pre-op, preoperative; POD, postoperative days; PBS, phosphate-buffered saline; PBMC, peripheral blood mononuclear cells; FCS, fetal calf serum; Err ratio, effector-to-target ratio this drug enhances the growth ofthe experimental metastases (8). Cisplatin (CDDP) and 5-fluorouracil (5-FU) are among the major agents which have been tested in clinical trials (2,9), and recently attention has turned to the combination therapy of low-dose CDDP-5-FU because of biochemical modulation (10,11).…”