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Medical Meeting Reports

American College of Surgery Clinical Congress

October 10-15, 1999

font=>By Paul Recchia, Ph.D.

Three leading research teams presented separate findings in surgical oncology research during a major Forum Series at the ACS meeting.

Potent Inhibition of Angiogenesis and Colon Cancer Liver Metastases

Angiogenesis is the dynamic process of new blood vessel formation from established vasculature. Vascular endothelial growth factor (VEGF) is a major stimulatory regulator of angiogenesis. Overexpression of VEGF and its endothelial cell receptor (Flk-1/KDR) has been associated with metastases from human colon cancer.

Lee M. Ellis, MD, University of Texas MD Anderson Cancer Center, and colleagues, hypothesized that inhibition of the tyrosine kinase (TK) activity of Flk-1/KDR could inhibit the growth of colon cancer liver metastases. Mice underwent splenic injection with colon cancer cells to generate liver metastases. After 4 days, 15 mice per group underwent daily injection of either a specific TK inhibitor for Flk-1/KDR (SU5416), or a TK inhibitor for the receptors for VEGF (SU6668). After 20 days of therapy, livers were weighed as a measure of tumor burden and processed for immunohistochemical analyses. SU5416 and SU6668 significantly inhibited the number of colon cancer liver metastases (48% and 55%, respectively), tumor vessel counts (42% and 36%), and cell proliferation (24% and 27%) relative to controls (P < 0.001). TK inhibitors targeting the VEGF receptor may have clinical utility in the management of colon cancer liver metastases.

Endostatin Produced by Cancer Cells Inhibits Formation of Lung and Liver Metastases

Tumors are dependent on angiogenesis for growth beyond 2 to 3 mm3 in size. Prior studies have demonstrated that endostatin, an antiangiogenesis factor, inhibits endothelial cell proliferation and induces regression of a wide variety of tumors grown subcutaneously in mice. The efficacy of endostatin on tumor formation in organ environments other than subcutaneous tissue is not well established.

Kenneth K. Tanabe, MD, of Massachusetts General Hospital and Harvard Medical School, and colleagues, demonstrated the effect of endostatin on the formation of lung and liver metastases. Mouse endostatin cDNA was subcloned into a mammalian expression vector. The resulting construct and the parent plasmid were transfected into RenCa mouse renal carcinoma cells and SW620 human colon carcinoma cells to create transfectant cell lines. To determine activity in vivo, cells from each stable transfectant cell line were injected into mice and tumor volume was assessed every 3 to 4 days. Conditioned serum-free medium from the RenCa and SW620 endostatin-transfectant cell lines inhibited proliferation by 41% to 50% and by 36% to 39%, respectively, as compared with conditioned medium from control-transfectant cell lines. Thus, endostatin inhibited the formation of lung and liver metastases.

Usefulness Of Molecular Markers In Early Breast Carcinoma

The use of adjuvant therapy in early breast carcinoma is controversial, with most advocating its use in high-risk patients. Recent studies have indicated that the final common pathway of chemotherapy-induced cytotoxic effects may be apoptosis; bcl-2, an inhibitor of apoptosis, is present in normal breast epithelium. Wild-type p53 can cause apoptosis. Mutant p53 expression correlates with a worse prognosis in a number of tumors as well as with decreased chemoresponsiveness.

Sarkis Meterissian, MD, of Royal Victoria Hospital and McGill University, and colleagues determined the prognostic value of bcl-2, and mutant p53 in stage Ic breast carcinoma. Disease-free survival and overall survival were determined in seventy-five patients with stage Ic breast carcinoma. Expression of mutant p53 was associated with a significant decrease in both 5-year disease-free survival (70% vs. 98%, P = 0.01) and 5-year overall survival (74% vs. 83%, P = 0.02). Fixed tissues were immunostained with bcl-2 antibodies. Pathologists evaluated stained slides. The results indicated that bcl-2 expression is a significant predictor of estrogen receptor status. Thus, bcl-2 expression could predict response to tamoxifen adjuvant therapy, whereas tumors expressing mutant p53 should be treated with chemotherapy.

Ortho Biotech

Funded through an unrestricted educational grant by Ortho Biotech.

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