© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 1803-1809, Copyright © 1997 by Oxford University Press
M Miyazaki, A Nagy, AV Schally, N Lamharzi, G Halmos, K Szepeshazi, K Groot and P Armatis
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.
ARTICLES
Growth inhibition of human ovarian cancers by cytotoxic analogues of luteinizing hormone-releasing hormone
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70146, USA.
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