Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice.
We tested the antineoplastic effect of the farnesyltransferase inhibitor L-744,832 in mammary and lymphoid tumors overexpressing the N-ras proto-oncogene in transgenic mice. Mice bearing mammary tumors were randomly assigned to receive daily 40 mg/kg s.c. injections of this compound (experimental group, n = 6) or vehicle (control group, n = 6) per day for 5.5 weeks. Treatment with the compound significantly reduced the mammary tumor mean growth rate in the experimental group (-0.7 mm3/day), as compared with the control group (+28.2 mm3/day; P < 0.001). There was a significant difference in lymphoma incidence at the end of the treatment between the experimental (0 of 6) and the control (3 of 6) groups (P < 0.05). Therefore, this compound is effective in treating in vivo mammary carcinomas and lymphomas in which an activated N-Ras pathway drives tumorigenesis. The number of apoptotic figures in mammary tumors was significantly higher (P = 0.04) in the experimental (14.7 +/- 8.1) than it was in the control (5.7 +/- 3.5) group, indicating that apoptotic induction could contribute to the mechanism of antitumor activity of this compound. We analyzed the level of processing of N-Ras and H-Ras after immunoprecipitation and Western blotting of protein extracts obtained from mammary tumors treated with L-744,832 or vehicle, either in vivo or in vitro (after primary culture of the same tumors), and from several in vitro treated control cell lines. In all compound-treated mammary tumors and cell lines, H-Ras was mostly unprocessed (more so after in vitro than after in vivo treatment), whereas N-Ras remained mostly processed. Both H-Ras and N-Ras remained fully processed in all vehicle-treated samples. These findings are consistent with a less intense antineoplastic effect of the treatment with the compound in our N-ras model than the effect previously reported for the same compound in H-ras transgenics. In addition, the finding that, in compound-treated mammary tumors, the N-Ras protein remains mainly processed suggests that, in our model, other proteins in addition to Ras may be a target for the compound. Our results and the previous findings of frequent N-ras activation in human hematopoietic malignancies support a role for L-744,832 in the treatment of lymphomas and of mammary carcinomas with an activated N-Ras pathway, as well as the testing of a farnesyl protein transferase inhibitor in humans to establish its clinical relevance.
Mangues
R
R
Department of Pathology and Kaplan Cancer Center, New York University Medical Center, New York 10016, USA.
Corral
T
T
Kohl
N E
NE
Symmans
W F
WF
Lu
S
S
Malumbres
M
M
Gibbs
J B
JB
Oliff
A
A
Pellicer
A
A
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D008223:Lymphoma / Q000188:drug therapy*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism*
D000970:Antineoplastic Agents; C096898:L 744832; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D016283:Proto-Oncogene Proteins p21(ras)