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OBJECTIVE: The aim of the study was to investigate the effects of the cytotoxic analog of luteinizing hormone-releasing hormone AN-207 on the growth of the OV-1063 human epithelial ovarian cancers, which express luteinizing hormone-releasing hormone receptor. AN-207 consists of doxorubicin derivative 2-pyrrolinodoxorubicin (AN-201) linked with the carrier [D-lysine6 ]luteinizing hormone-releasing hormone. STUDY DESIGN: Female nude mice bearing xenografts of OV-1063 ovarian cancers were treated with analog AN-207, cytotoxic radical AN-201, or agonist [D-lysine6 ]luteinizing hormone-releasing hormone. The levels and expression of messenger ribonucleic acid of receptors for luteinizing hormone-releasing hormone and epidermal growth factor were evaluated. RESULTS: The growth of OV-1063 tumor was significantly inhibited by 3 to 5 nmol AN- 207 but not by [D-lysine6 ]luteinizing hormone-releasing hormone. Cytotoxic radical AN-201 was toxic at these doses. After treatment with AN-207 receptors for luteinizing hormone-releasing hormone were not detectable, epidermal growth factor receptor levels declined, and expressions of their respective messenger ribonucleic acids were decreased. CONCLUSIONS: Targeted cytotoxic luteinizing hormone-releasing hormone analog AN-207 is less toxic than equimolar doses of its radical 2-pyrrolinodoxorubicin and effectively inhibits ovarian tumor growth. Targeted chemotherapy may improve management of ovarian cancer.
In bullfrog sympathetic ganglia, the ryanodine-sensitive Ca2+ store and mitochondria modulate [Ca2+] within nerve terminals. We used caffeine (10 mM) and carbonyl cyanide m-chlorophenylhydrazone (10 microM) to assess how these Ca2+ stores affect release of a neuropeptide, luteinizing hormone-releasing hormone, from these nerve terminals. Release of luteinizing hormone-releasing hormone was evoked by electrical stimulation to presynaptic nerves and was monitored as a late slow excitatory postsynaptic potential in ganglionic neurons. Caffeine increased release of luteinizing hormone-releasing hormone similarly whether the release was evoked by 4 or 20 Hz stimulations (by 2.7 +/- 1.1- and 3.2 +/- 0.9-fold, mean +/- S.E.M., n = 27, respectively). Carbonyl cyanide m-chlorophenylhydrazone augmented release of luteinizing hormone-releasing hormone evoked by 4 Hz stimulation much more strongly (by 11.8 +/- 1.8-fold) than it increased the release evoked by 20 Hz stimulation (by 3.6 +/- 1.3-fold, n = 25). We detected spontaneous release of luteinizing hormone-releasing hormone as a slow hyperpolarization in response to a brief application of an antagonist to the receptors for luteinizing hormone-releasing hormone in 65% (34 of 52) and 39% (11 of 28) of the ganglionic B and C neurons, respectively. Caffeine increased spontaneous release of luteinizing hormone-releasing hormone by 2.3 +/- 0.7-fold (n = 6) whereas carbonyl cyanide m-chlorophenylhydrazone increased this release by 4.27- and 1.76-fold (n = 2). Facilitation of Ca2+ release from the intracellular store by caffeine and inhibition of mitochondrial Ca2+ removal by carbonyl cyanide m-chlorophenylhydrazone increased spontaneous as well as evoked release of luteinizing hormone-releasing hormone. Moreover, caffeine increments of evoked release did not depend on the firing frequency of the nerve whereas carbonyl cyanide m-chlorophenylhydrazone augmentations of evoked release strongly depended on the firing frequency.