Effects of the farnesyl transferase inhibitor R115777 (Zarnestra) on mammary carcinogenesis: prevention, therapy, and role of HaRas mutations.
The ability of the farnesyl transferase inhibitor R115777 to act as a cancer therapeutic/preventive agent and to modulate proliferation/apoptosis markers was determined in the methylnitrosourea-induced model of mammary carcinogenesis. Female Sprague-Dawley rats were given methylnitrosourea at 50 days of age. In the prevention study, R115777 (5, 16, or 50 mg/kg body weight/d), beginning 5 days after methylnitrosourea treatment, decreased the formation of mammary cancers by 6%, 42%, and 75%, respectively. Approximately 50% of the mammary cancers that developed had HaRas mutations. Only 1 of 15 tumors that grew out in the presence of R115777 (16 or 50 mg/kg body weight/d) had a HaRas mutation. In the therapeutic study, a surgical biopsy of a mammary cancer was done to determine HaRas status, and growth of the cancer was then followed during treatment of the rat with R115777. Virtually every cancer with a HaRas mutation underwent complete regression within 3 weeks, whereas tumors without a HaRas mutation had variable responses to the inhibitor. Both of these studies implied a high sensitivity of tumors with HaRas mutations to the effects of R115777. In order to understand the preferential susceptibility of tumors with HaRas mutations, rats with a palpable cancer were treated with R115777 for a period of 36 or 96 hours prior to sacrifice, and the proliferation and apoptosis levels in the cancers were determined. The proliferative index was significantly (>85%) decreased in all mammary cancers with HaRas mutations, whereas variable responses were observed in cancers without HaRas mutations. Apoptosis was also measured and a 5-fold increase was observed in HaRas mutant tumors, again with varying responses in the HaRas wild-type cancers. Thus, R115777 was active in the prevention and therapy of these chemically induced mammary cancers, but was strikingly more effective in cancers with HaRas mutations.
Lubet
Ronald A
RA
National Cancer Institute, Executive Plaza North, Suite 2110, 6130 Executive Boulevard, Bethesda, MD 20852, USA. lubetr@mail.nih.gov
Christov
Konstantin
K
You
Ming
M
Yao
Ruisheng
R
Steele
Vernon E
VE
End
David W
DW
Juliana
M Margaret
MM
Grubbs
Clinton J
CJ
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D016587:Antimutagenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D011905:Genes, ras / Q000187:drug effects*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology* / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016588:Anticarcinogenic Agents; D016587:Antimutagenic Agents; D002273:Carcinogens; D004791:Enzyme Inhibitors; D015363:Quinolones; D008770:Methylnitrosourea; D051231:Farnesyltranstransferase; C402769:tipifarnib