Everett V. Sugarbaker

Synergistic induction of apoptosis in breast cancer cells by tamoxifen and calmodulin inhibitors

Breast cancer cells are relatively resistant to the induction of apoptosis (AP) and drug regimens which readily activate apoptotic death, may enhance the antitumor effect. Rapid and intensive induction of apoptosis was observed in estrogen receptor positive and negative breast cancer cell cultures treated with tamoxifen (TMX) combined with the calmodulin antagonists trifluoperazine (TFP) or W7. TMX (1-5 microM) alone or calmodulin antagonists alone did not induce apoptosis. Importantly, intensive apoptosis was also induced by TMX and TFP in the cells obtained from primary human breast carcinomas. Inhibition of the Ca2+ calmodulin signaling pathway is an effective way to activate apoptotic death in epithelial cells. Combination of TMX with non-toxic calmodulin inhibitors may increase the preventive and therapeutic effects of TMX.

Correlation of cell cycle analysis with Duke's staging in colon cancer patients

The biologic potential of a tumor for growth and metastasis is relatively inaccurately mirrored by the present staging system in colon cancers [29]. Except for Stage IV disease, traditional morphologic criteria approaches only 50-75% accuracy for predicting recurrent disease. Reliable staging, however, has become more critical in the light of the current thrust in adjuvant therapy research. First, the patients receive toxic and expensive therapy. Second, and of even greater importance, a central tenet of adjuvant therapy research is that treatment and control groups under study are comparable. Inadequate staging not only undermines analysis, especially when small improvements of lo-20% may be expected, but also demands very large study groups to offset this defect. A significant amount of research has attempted to quantitate the metastatic potential of a tumor. In the animal model some factors such as cell adhesiveness, tumor angiogenesis, detachability, thromboplasticity, and shedding of membrane antigen have been associated with an increased propensity of a tumor to spread [23]. In the clinical forum, analysis of factors such as tumor grade [4, 71, vascular invasion [7], host immune status [ 1, 8, 91 have not been established as having a clear-cut prognostic value. Hopefully prospective studies, objective criteria, and more sophisticated statistical analysis [6] may yield less disappointing results in the future. In this respect, accumulating evidence indicates that the analysis of tumor kinetics will be a major determinant of the metastatic potential of a tumor. It is well established that kinetic data of tumor doubling time and labeling index (LI) is associated with length of survival [ 11, 18, 21, 271, but the effect of tumor doubling time on ultimate survival was reported by Joseph et al. [12, 161. In his report, patients with resection of solitary pulmonary metastasis with doubling times less than 40 days subsequently died of metastasis whereas 60% of the patients with tumor doubling time over 40 days were cured. Other measures of tumor proliferative activity, i.e, mitotic index in sarcomas 1281 and labeling index in breast cancer patients 1151 have recently been implicated as important prognostic determinants, and in the former instance has been incorporated into the A.J.C. stating system [20] as a factor influencing tumor grading. Finally, the development of flow cytometry [24] has now made the rapid and objective analysis of cell cycle kinetics an exciting clinical reality. In this study, the predictive potential of cell cycle analysis by flow cytometry was examined by comparing the proliferative activity of colorectal adenocarcinoma with Duke’s staging and modified Broder’s grading.

An examination of the macrophage response after challenge with murine, syngeneic sarcoma cells

Abstract The role that macrophages play in the reticuloendothelial organs may be an important determinant in tumor progression. Enzymatic staining for lipase activity was used in this study to quantitate macrophage infiltrates of primary tumors, metastases, spleens, and thymuses during progressive tumor growth and metastasis utilizing an MCA-induced, syngeneic, antigenic, spontaneously metastasizing murine sarcoma. After a single im injection of sarcoma tumor cells, the red pulp, but not the white pulp, of the spleens showed a progressive increase of macrophages as the tumors grew. Correspondingly, colonies of macrophages appeared in the thymuses of mice with tumor growth. Prior to the appearance of macrophage colonies in the thymus, a significant depression in the number of spleen and thymus cells undergoing DNA synthesis was seen. Infiltration of macrophages was scarcely seen in either the original MCA-induced or transplanted sarcomas regardless of tumor size. The development of lung metastases was dependent on the primary tumor size before amputation of the tumor-bearing legs. The pulmonary metastases that developed from mice that had their primary tumors amputated at a metastasizing size were void of macrophages regardless of metastatic size (1–10 mm diameter). If the primary tumor-bearing legs were amputated at a premetastasizing size, the macrophage activity in the spleen and thymus decreased to control levels within 2 weeks. However, if the tumors were allowed to grow to metastasizing sizes, the macrophage activity in the spleens and thymuses did not decrease after amputation.

The effects of syngeneic soluble tumor membrane extract on concomitant spleen cell immunity and spontaneous metastases

The effects of a soluble tumor KCl extract, containing membrane antigen on spontaneous metastases and spleen cell immunity were studied in a syngeneic C57BL/6J murine sarcoma model. The extract was shown to be antigenically distinct from normal tissue by tumor immunization rejection experiments. Tumor soluble extract (SE) was administered daily during the growth of a murine sarcoma. The afferent and efferent arc of immunity were monitored by proliferative index (PI) and in vitro cytotoxicity of spleen cells, as well as the incidence of metastases. PI was significantly activated in the group receiving sarcoma SE as compared to the two control groups receiving muscle SE or saline P less than 0.05. However, in vitro cytotoxicity was significantly depressed on Days 7 and 14 (P less than 0.05) of tumor growth in the mice receiving sarcoma SE. The incidence of metastases was significantly increased to 70% in the sarcoma SE group as compared to the incidence in the control groups of 50% P less than 0.05. This data supports the hypothesis that release of soluble antigen membrane components by growing tumor facilitates the growth of metastases in this model.