Acceleration of tumor growth and peri-tumoral blood clotting by imatinib mesylate (Gleevec).
Imatinib mesylate (Gleevec) inhibits the BCR-ABL tyrosine kinase in chronic granulocytic leukemia. Previous studies have demonstrated that imatinib mesylate also inhibits the survival and functions of normal mast cells by interfering with the receptor tyrosine kinase for stem cell factor (SCF), c-kit, which is expressed by mast cells. Because mast cells extensively surround many types of cancer and contain powerful anticoagulants such as heparin, we investigated the effects of imatinib mesylate on blood clotting and tumor growth within subcutaneous implants of a mammary adenocarcinoma cell line (4T1) in BALB/c mice. After 5 days of oral treatment with 10 mg/kg of the drug, the average mass of the tumors in treated mice (198 +/- 42 mg, n = 5) was significantly (p < 0.05) greater than the average mass of the tumors from untreated (control) mice (60 +/- 23 mg, n = 5). Moreover, the tumors in the treated mice were frequently surrounded by large lakes of clotted blood that were not evident in tumors from the control mice. Accelerated growth and blood clotting were also observed in tumor-bearing mice treated with heparinase I enzyme to destroy endogenous mast cell heparin and in NDST-2 knockout mice in which there is a targeted disruption in the gene coding for mast cell heparin synthesis. We conclude that imatinib mesylate accelerated the growth and peri-tumoral blood clotting of implants of mammary adenocarcinoma in mice. These results suggest that imatinib mesylate may have significant effects on mast cells infiltrating tumors, in addition to its other biologic activities. Our results also indicate that the mechanism of this effect may be related to the anticoagulant properties of mast cell heparin.
Samoszuk
Michael
M
Pathology Department, University of California Irvine Medical Center, Orange, CA 92868, USA. msamoszu@uci.edu
Corwin
Mark A
MA
D000230:Adenocarcinoma / Q000097:blood* / Q000473:pathology; D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001777:Blood Coagulation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D019763:Heparin Lyase / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008325:Mammary Neoplasms, Experimental / Q000097:blood* / Q000473:pathology; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000925:Anticoagulants; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D006493:Heparin; D011505:Protein-Tyrosine Kinases; C113066:NDST2 protein, human; C491855:Ndst2 protein, mouse; D015238:Sulfotransferases; D000581:Amidohydrolases; D019763:Heparin Lyase