Treatment of experimental DMBA induced mammary carcinoma with Cetrorelix (SB-75): a potent antagonist of luteinizing hormone-releasing hormone.
Cetrorelix, (Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10)-LHRH (SB-75) is a new highly potent antagonist of LH-RH. In the model of DMBA-induced mammary carcinoma, this antagonist was very effective in reducing tumor mass. A rapid decrease in tumor weights to levels below 0.1 g total tumor mass was achieved with 300 micrograms/kg given sc. daily for 14 days. The weights of uteri and ovaries were reduced to about 40-50% of control values. In all treated rats the estrus cycle was interrupted and the animals remained in a state of anestrus. Microscopically, the effects of Cetrorelix on the tumors were characterized by a loss of mitotic activity, marked regression with apoptosis, an increase of stroma and differentiation towards a normal mammary architecture. On the basis of a dose-response curve, a dose of 100 micrograms/kg/d of Cetrorelix was determined as sufficient for a full antitumor response. Large DMBA-tumors with total tumor mass of about 6 g could also be treated very effectively with a dose of 100 micrograms/kg/d. To achieve a complete tumor regression, the treatment had to last 34 days. After the cessation of treatment with 100 micrograms/kg/d and regrowth of the tumors the animals were treated with the agonist Decapeptyl (Trp6-LHRH) using a dose of 50 micrograms/rat/d for 14 days. Again, the tumors responded well and regressed within 10 days. The treatment with an overlapping dose schedule of Cetrorelix and Decapeptyl showed a continuous antitumor response. A transient stimulation of tumor growth by the LH-RH agonist was not observed under these experimental conditions. In ovariectomized rats bearing DMBA-tumors, treatment with Cetrorelix and estradiol, produced no tumor growth inhibition as compared to estradiol control group, indicating that there is no estrogen nullifying effect of this antagonist on tumor cells in this model. On the basis of these results, Cetrorelix is a highly effective antitumor agent in this breast cancer model, which might also be useful under clinical conditions.
Reissmann
T
T
ASTA Pharma AG, Frankfurt, Federal Republic of Germany.
Hilgard
P
P
Harleman
J H
JH
Engel
J
J
Comaru-Schally
A M
AM
Schally
A V
AV
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D017329:Triptorelin Pamoate
D000970:Antineoplastic Agents; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D015127:9,10-Dimethyl-1,2-benzanthracene; C062876:cetrorelix