Prevention of rat mammary carcinoma utilizing leuprolide as an equivalent to oophorectomy.
A clinical trial is currently under way to examine the effectiveness of leuprolide as a breast cancer chemopreventive agent and contraceptive. This trial, as well as similar proposed studies, is based on the assumption that leuprolide is as effective as surgical castration in preventing the onset of mammary tumors; however, this has not been well documented in the DMBA animal model. We directly compared leuprolide and oophorectomy in this model and examined a combined therapy of leuprolide/bromocriptine. Twenty-seven day old female Sprague-Dawley rats were randomly allocated into one of eight groups. All rats received a 20-mg dose of DMBA at the age of 55 days. Group 1 (n = 10), no treatment; Group 2 (n = 9), leuprolide (100 microg/kg/day) for eight weeks beginning four weeks prior to DMBA; Group 3 (n = 10), oophorectomy four weeks prior to DMBA with replacement estrogen beginning four weeks following DMBA. Estrogen replacement was achieved with a 0.05-mg estradiol tablet releasing 0.833 microg/day over a 60-day period. Group 4 (n = 10), leuprolide (100 microg/kg/day) initiated two weeks prior to DMBA and continuing for two weeks following DMBA; Group 5 (n = 9), oophorectomy two weeks prior to DMBA with 0.05 mg of estradiol in depot form, releasing 0.833 microg/day, beginning four weeks following DMBA and continuing until week 16 of the study; Group 6 (n = 10), leuprolide (100 microg/kg/day) beginning two weeks prior to DMBA and continuing for the duration of the experiment; Group 7 (n = 10), leuprolide (100 microg/kg/day) for eight weeks beginning two weeks prior to DMBA; Group 8 (n = 9), leuprolide (100 microg/kg/day) and bromocriptine (83 microg/day) for eight weeks beginning two weeks prior to DMBA. At nineteen weeks (15 weeks post DMBA), animals were sacrificed and autopsies performed. One hundred percent of untreated animals developed tumors. No animals undergoing oophorectomy four weeks prior to DMBA or receiving leuprolide four weeks prior to and simultaneously with DMBA developed tumors. In animals pretreated two weeks prior to DMBA with leuprolide or oophorectomy, each group had one animal with tumor development. No tumors developed in the animals receiving ongoing injections of leuprolide. However, one tumor developed in those receiving leuprolide for the first eight weeks beginning two weeks prior to DMBA administration. One animal receiving both leuprolide and bromocriptine developed one tumor. We conclude that chemical oophorectomy (with leuprolide) is as effective as surgical oophorectomy in inhibiting DMBA induced carcinogenesis.
Jett
E A
EA
Department of Surgery, University of Oklahoma Health Science Center, Oklahoma City, USA.
Lerner
M R
MR
Lightfoot
S A
SA
Hanas
J S
JS
Brackett
D J
DJ
Hollingsworth
A B
AB
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D002273:Carcinogens; D004195:Disease Models, Animal; D005260:Female; D016729:Leuprolide / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control*; D010052:Ovariectomy; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D018931:Antineoplastic Agents, Hormonal; D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; D016729:Leuprolide