Combination therapy including a gelatinase inhibitor and cytotoxic agent reduces local invasion and metastasis of murine Lewis lung carcinoma.
The efficacy of combination therapy including an oral gelatinase inhibitor (CT1746) and cytotoxic agent was analyzed using the murine Lewis lung carcinoma model. Primary tumors, pulmonary metastases, and sera from tumor-bearing animals had increased gelatinase B activity that was inhibited by CT1746 levels achievable in vivo. The combination of CT1746 and cyclophosphamide (CTX) was significantly more effective than either single agent in delaying local tumor growth (CT1746/CTX, 30.9 +/- 1.7 days; CT1746, 2.6 +/- 0.3 days; CTX, 19.5 +/- 1.1 days; P < .001) and reducing the number and size of pulmonary metastases [CT1746/CTX, 5 +/- 2 (15% metastases > 3 mm); CT1746, 15 +/- 4 (55% > 3 mm); CTX, 11 +/- 3 (63% > 3 mm); no treatment, 24 +/- 5 (62% > 3 mm); P < .001]. These data support the notion of combining matrix metalloproteinase inhibitors and cytotoxic agents to treat certain epithelial malignancies.
Anderson
I C
IC
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Shipp
M A
MA
Docherty
A J
AJ
Teicher
B A
BA
D000577:Amides / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use*; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis
D000577:Amides; C099496:CT 1746; D003520:Cyclophosphamide; D018093:Gelatinases; D002945:Cisplatin