Growth inhibition of human ovarian cancers by cytotoxic analogues of luteinizing hormone-releasing hormone.

Abstract

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.

• Authors: M Miyazaki, A Nagy, A V Schally, N Lamharzi, G Halmos, K Szepeshazi, K Groot, P Armatis
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 89 Issue 23 Pg. 1803-9 (Dec 03 1997) ISSN: 0027-8874 [Print] United States
• PMID: 9392622 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• RNA, Messenger
• RNA, Neoplasm
• Receptors, LHRH
• LHRH, lysine(6)-doxorubicin
• Gonadotropin-Releasing Hormone
• Epidermal Growth Factor
• Doxorubicin
• Luteinizing Hormone
• ErbB Receptors

Topics

• Animals
• Antibiotics, Antineoplastic (therapeutic use)
• Apoptosis (drug effects)
• Blotting, Southern
• Carcinoma (drug therapy, metabolism)
• Doxorubicin (analogs & derivatives, therapeutic use)
• Epidermal Growth Factor (blood, genetics)
• ErbB Receptors (genetics)
• Female
• Gonadotropin-Releasing Hormone (analogs & derivatives, therapeutic use)
• Humans
• Luteinizing Hormone (blood, genetics)
• Mice
• Mice, Nude
• Mitotic Index (drug effects)
• Ovarian Neoplasms (drug therapy, metabolism)
• Polymerase Chain Reaction (methods)
• RNA, Messenger (analysis)
• RNA, Neoplasm (analysis)
• Receptors, LHRH (drug effects, metabolism)
• Transcription, Genetic
• Tumor Cells, Cultured