The matrix metalloproteinase inhibitor batimastat (BB-94) retards human breast cancer solid tumor growth but not ascites formation in nude mice.
Matrix metalloproteinases (MMPs) are thought to play a significant role in tumor invasion and metastasis as well as angiogenesis. Batimastat, also known as BB-94, acts as an inhibitor of metalloproteinase activity by binding the zinc ion in the active site of MMPs. In our study, the hormone-independent MDA435/LCC6 human breast cancer cell line was used to seed solid tumors s.c. into the region of the mammary fat pad in athymic nude mice. Mice were treated with 50 mg/kg batimastat i.p. Tumor volume measurements showed a statistically significant decrease in tumor size between batimastat-treated and control animals. In contrast, we also used the same MDA435/LCC6 cell line to propagate a malignant ascites in nude mice, which yielded a very different response to batimastat. Batimastat, in previously published literature, had been shown to prolong the life of mice bearing ovarian ascites tumors. Treatment with batimastat in our ascites model produced no increase in survival or significant suppression of ascites formation. However, treated animals showed dramatic tumor cell consolidation and less dispersed ascites cells compared with control animals. Two potential targets of batimastat, gelatinase A and B (MMP-2 and -9, respectively), were examined in both tumor sites. These metalloproteinases were present in both solid tumor and ascites fluid and in both cases were host derived and not produced by the tumor. We conclude that batimastat may have different effects on tumor progression and growth depending on the site of tumor implantation.
Low
J A
JA
Departments of Cell Biology, Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, D. C. 20007, and British Biotech, Ltd., Oxford OX4 5LY, United Kingdom.
Johnson
M D
MD
Bone
E A
EA
Dickson
R B
RB
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001201:Ascites / Q000517:prevention & control*; D005260:Female; D018093:Gelatinases / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D018093:Gelatinases; D008666:Metalloendopeptidases