Growth inhibition of human ovarian cancers by cytotoxic analogues of luteinizing hormone-releasing hormone.
BACKGROUND
Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in nearly 80% of human ovarian cancers. The chemotherapeutic agent doxorubicin can be linked to [D-lysine6]LH-RH to form a cytotoxic analogue (AN-152) that may have greater specificity for tumor cells. This study was conducted to investigate the effects of AN-152 on the growth of LH-RH receptor-positive OV-1063 human epithelial ovarian cancers.


METHODS
Nude mice bearing human ovarian tumors, OV-1063 or UCI-107 (LH-RH receptor negative), were injected intraperitoneally with saline (control) or with equimolar doses of AN-152 or doxorubicin; experiments involving mice with OV-1063 tumors also included groups that were administered [D-lysine6]LH-RH either alone or in combination with doxorubicin. Tumor volume, weight, doubling time, and burden (i.e., tumor weight/body weight) as well as tumor apoptotic and mitotic indices were determined. The levels of receptors for LH-RH and epidermal growth factor (EGF) and their messenger RNAs were measured by use of radioreceptor and reverse transcription-polymerase chain reaction assays, respectively.


RESULTS
The growth of OV-1063 ovarian tumors in nude mice, as based on reduction in tumor volume, was inhibited significantly (all P<.05, two-sided) 4 weeks after treatment with AN-152, even at the lowest dose tested (413 nmol/20 g weight); the toxic effects of an equivalent dose of doxorubicin caused substantial mortality. High-affinity receptors for LH-RH and EGF were found on cell membranes of OV-1063 cancers; however, after in vivo treatment with AN-152, LH-RH receptor-binding sites were not detectable and EGF receptors were reduced in number. The growth of UCI-107 ovarian cancers was not inhibited by AN-152.


CONCLUSIONS
In nude mice bearing LH-RH receptor positive OV-1063 epithelial ovarian cancers, systemic administration of AN-152 is less toxic and inhibits tumor growth better than equimolar doses of doxorubicin.
Miyazaki
M
M
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70146, USA.
Nagy
A
A
Schally
A V
AV
Lamharzi
N
N
Halmos
G
G
Szepeshazi
K
K
Groot
K
K
Armatis
P
P
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015139:Blotting, Southern; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004815:Epidermal Growth Factor / Q000097:blood / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008940:Mitotic Index / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D011966:Receptors, LHRH / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011966:Receptors, LHRH; C080883:LHRH, lysine(6)-doxorubicin; D007987:Gonadotropin-Releasing Hormone; D004815:Epidermal Growth Factor; D004317:Doxorubicin; D007986:Luteinizing Hormone; D066246:ErbB Receptors