Primary Tumor Growth Rate Research Articles

Indomethacin therapy abrogates the prostaglandin-mediated suppression of natural killer activity in tumor-bearing mice and prevents tumor metastasis

We have shown earlier that a decline in splenic natural killer (NK) activity during the development of transplanted or spontaneous tumors in mice results from an inactivation of NK lineage cells, mediated by prostaglandins (primarily PGE 2) secreted by NK suppressor cells of the monocyte-macrophage lineage. In the present study we have used a C3H mouse mammary carcinoma model to examine (a) whether this mechanism of NK suppression is conducive to tumor metastasis in vivo and (b) whether a reversal of this suppression by a chronic indomethacin therapy can prevent metastatic spread from the primary tumor site. Three mammary tumor lines, all derived in our laboratory from a spontaneous C3H mammary tumor were employed: T-58 (uncloned parental line, having weak lung metastasizing ability from the subcutaneous site), C3 (a clone of T-58, showing high metastatic ability), and C10 (a nonmetastatic clone of T-58). Although the degree of NK susceptibility of these lines varied inversely with their metastatic potential, none was NK resistant. A chronic administration of indomethacin in the drinking water (14 μg/ml) to mice beginning on Day 4 after subcutaneous transplantation of 10 6 tumor cells resulted in a significant reduction in the growth rate of primary tumors in all hosts and led to a complete or nearly complete abrogation of lung metastasis in T-58- or C3-transplanted hosts examined at 1 month after tumor transplantation; C10-transplanted mice showed no metastasis in the control or the treated group. Concomitantly, there was a substantial restoration of splenic NK activity in all indomethacin-treated hosts. Plastic-adherent cells (>95% macrophages) isolated from tumors growing in control mice, when coincubated for 20 hr with normal splenic effector cells caused a suppression of NK activity, reversible in the presence of indomethacin (10 −5 M) in vitro. Similar cells recovered from the residual primary tumors in indomethacin-treated mice had no suppressor ability. Chemically pure PGE 2 (at concentrations of 0.5 to 1 × 10 −6 M, but not 0.25 × 10 −6 to 10 −8 M) also caused a suppression of NK activity of normal splenic effector cells, when added during the 4-hr 51Cr-release assay or allowed to interact with effector cells alone for a 20-hr incubation period; a removal of the cell-free PGE2 in the latter case prior to the NK assay did not relieve the suppression. These results suggest that prostaglandin-mediated inactivation of natural killer (or other potential killer) cells by host macrophages may promote spread of metastasizable tumor cells to distant organs, and its reversal with indomethacin therapy can control metastasis.

Effect of alpha-difluoromethylornithine in lung metastases before and after surgery of primary adenocarcinoma tumors in mice.

The depletion of polyamines by alpha-difluoromethylornithine (DFMO) treatment of mice after subcutaneous inoculation of adenocarcinoma M3 cells caused a remarkable inhibition in the growth rate of primary tumors as well as in the occurrence and number of lung metastases with a concomitant increase in survival time. Tumor-bearing mice submitted to the surgical removal of primary tumors and then treated with alpha-difluoromethylornithine also showed a significant reduction of lung metastases. In addition, a lower number of lung metastatic nodules correlated with decreased levels of polyamines in the same tissue. The described approach provides a useful experimental model for studies in human cancer therapy.

Influence of Dietary Fatty Acid Concentration and Geometric Configuration on Murine Mammary Tumorigenesis and Experimental Metastasis

To investigate the influence of fatty acid geometric isomers on the growth and experimental metastasis of mammary tumors, mice were fed diets containing fat high in either cis or trans fatty acids. The cis fat was prepared to have a fatty acid composition similar to that of the trans fat; both were provided at 5 or 20% (by weight) of the diet. Line 168 mammary tumor cells were transplanted: 1) subcutaneously into female BALB/c mice to observe the effects of dietary fat on latency and local tumor growth, and 2) intravenously to observe influences on experimental metastasis. No differences in the latency or rate of primary tumor growth were observed among the groups fed the diets containing cis or trans fatty acids. In addition, there were no differences in fatty acid composition except the levels of trans-C18:1 in the primary tumor cells among the groups fed the experimental diets. Livers and spleens from animals fed both the 5 and 20% cis diet contained significantly more viable radiolabeled tumor cells than those fed the trans diets. Although body weight and composition were not significantly different among the groups, livers from animals fed the diets containing trans fatty acids were significantly heavier than those fed diets containing only cis fatty acids. Thus, trans fatty acids behaved similarly to cis fatty acids with respect to promotion of transplantable mammary tumor growth but trans fatty acids were less effective than cis fatty acids in promoting the blood-borne implantation and distant survival of the tumor cells.

Suppressor Cells and Increased Primary Tumor Growth Rate Induced by Thiopental

A single dose of thiopental (37-42 mg/kg) sufficient to achieve anesthesia induction increased the growth rate of a 3-methylcholanthrene-induced syngeneic murine fibrosarcoma in C57B1/6 mice. While no alterations in in vitro growth kinetics of tumor cells cultured with thiopental could explain these data, significant alterations in cell-mediated immunity were observed. Spleen cells from C57B1/6 mice treated with thiopental were impaired in their ability to respond in a mixed leukocyte culture (MLC) to BALB/c stimulator cells. Spleen cells from thiopental-treated mice suppressed the ability of cells from untreated animals to respond in a third-party MLC. The degree of suppression was directly proportional to the number of cells from thiopental-treated mice in the third party. When these cells were added to an MLC at various times during the culture period, suppression of the early phases of the MLC was seen. Removal of plastic adherent cells from the third party resulted in loss of suppression, but treatment of third-party cells with anti-thy 1.2 serum or irradiation did not prevent suppression. Transfer of spleen cells from thiopental-treated mice enhances growth of the B-16 melanoma. Suppressor-cell activity may be one mechanism by which thiopental promotes tumor growth.

Suppressor cells and increased primary tumor growth rate induced by thiopental.

A single dose of thiopental (37-42 mg/kg) sufficient to achieve anesthesia induction increased the growth rate of a 3-methylcholanthrene-induced syngeneic murine fibrosarcoma in C57B1/6 mice. While no alterations in in vitro growth kinetics of tumor cells cultured with thiopental could explain these data, significant alterations in cell-mediated immunity were observed. Spleen cells from C57B1/6 mice treated with thiopental were impaired in their ability to respond in a mixed leukocyte culture (MLC) to BALB/c stimulator cells. Spleen cells from thiopental-treated mice suppressed the ability of cells from untreated animals to respond in a third-party MLC. The degree of suppression was directly proportional to the number of cells from thiopental-treated mice in the third party. When these cells were added to an MLC at various times during the culture period, suppression of the early phases of the MLC was seen. Removal of plastic adherent cells from the third party resulted in loss of suppression, but treatment of third-party cells with anti-thy 1.2 serum or irradiation did not prevent suppression. Transfer of spleen cells from thiopental-treated mice enhances growth of the B-16 melanoma. Suppressor-cell activity may be one mechanism by which thiopental promotes tumor growth.

Selenium-mediated inhibition of mouse mammary tumorigenesis

The effects of selenium on mouse mammary tumorigenesis were examined in 2 systems. BALB cfC3H (MuMTV-S positive) given 2 and 6 ppm selenium in the drinking water and maintained as breeding mice, had significantly lower incidences of mammary tumors (48% and 12%, respectively) than untreated control mice (82%). Selenium at 4 ppm inhibited the tumor-producing capabilities of only 1 of 4 preneoplastic outgrowth lines maintained in BALB c (MuMTV-S negative) mice. Selenium at 2, 4 and 6 ppm had no effect on the growth rate of primary mammary tumors transplanted subcutaneously in BALB c mice. Selenium inhibited mammary tumorigenesis without interference of normal reproductive function and weight gain.

Facilitated metastatic distribution of the Walker 256 tumor in Sprague-Dawley rats with hydrocortisone and-or cyclophosphamide.

AbstractThe strain of Walker 256 tumor studied metastasized readily and preferentially to the lungs. Cyclophosphamide or hydrocortisone significantly increases extrapulmonary metastasis formation when 'cytostatic' therapy is begun when the primary tumor has reached 2.0‐2.5 cm in size. Drug mortality excluded, survival in animals treated with cyclophosphamide decreases despite a temporary retardation of the primary tumor growth rate. This decreased survival correlates with an increase in the number of pulmonary metastases and more widespread organ distribution of metastases. It is hypothesized that suppression of the host immune response by an alkylating agent and/or hydrocortisone was the likely mechanism involved, although localization of tumor cells at sites of chemical inflammation and other mechanisms have not been excluded. These data provide ancillary evidence for the hypothesis that the immune mechanism controls, at least in part, the formation of metastasis from circulating and/ or dormant tumor cells, particularly in organs which are not sites of preferential metastasis.