title: Therapy of ovarian cancers with targeted cytotoxic analogs of bombesin, somatostatin, and luteinizing hormone-releasing hormone and their combinations.
abstract: The aim of this study was to investigate the effect of treatment of experimental ovarian cancers with targeted cytotoxic analogs as single compounds and in combination. Targeted cytotoxic analogs of bombesin (AN-215), somatostatin (AN-238), and luteinizing hormone-releasing hormone (AN-207) consisted of 2-pyrrolinodoxorubicin (AN-201) linked to the respective peptide carrier. AN-238 at 200 nmol/kg significantly inhibited growth of UCI-107, ES-2 and OV-1063 ovarian cancers. AN-215 alone at 200 nmol/kg and its combination with AN-238 at one-half of the dose were also able to inhibit the growth of UCI-107 tumors. A combination of AN-238 with AN-207at 50% of the dose strongly suppressed the proliferation of ES-2 and OV-1063 ovarian tumors. Cytotoxic radical AN-201 was toxic and had no significant effect on tumor growth. In contrast, the toxicity of the conjugated peptide analogs was low. Because ovarian cancers tend to acquire chemoresistance, we used real-time PCR to measure the mRNA expression of multidrug resistance protein 1, multidrug resistance-related protein 1, and breast cancer resistance protein after treatment. Low or no induction of multidrug resistance protein 1, multidrug resistance-related protein, and breast cancer resistance protein occurred after treatment with AN-238, AN-215, and the combination of AN-238 with AN-207 or AN-215. These results demonstrate that a therapy with cytotoxic analogs such as single agents and combinations is effective and nontoxic. Our work suggests that cytotoxic peptide analogs of luteinizing hormone-releasing hormone, somatostatin, and bombesin could be used for the therapy of ovarian cancers, considering the lack of induction of chemoresistance.
authors.affiliation: *Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112.|Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Universität Regensburg, Landshuterstraße 65, 93051 Regensburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Buchholz
authors.affiliation: *Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112.|Universitätsklinik für Haut- und Geschlechtskranheiten, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany; and.
authors.forename: Gunhild
authors.initials: G
authors.lastname: Keller
authors.affiliation: *Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112; andrew.schally@va.gov.|Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, 1201 Northwest 16th Street, Miami, FL 33125.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: *Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112.
authors.forename: Gabor
authors.initials: G
authors.lastname: Halmos
authors.affiliation: *Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112.
authors.forename: Florian
authors.initials: F
authors.lastname: Hohla
authors.affiliation: *Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112.
authors.forename: Elmar
authors.initials: E
authors.lastname: Heinrich
authors.affiliation: *Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112.
authors.forename: Frank
authors.initials: F
authors.lastname: Koester
authors.affiliation: *Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Baker
authors.affiliation: *Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112.|Universitätsfrauenklinik Würzburg, Josef-Schneider-Strasse 4, 97080 Würzburg, Germany.
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Engel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001839:Bombesin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004359:Drug Therapy, Combination; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D014975:Lutein / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger; D013004:Somatostatin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D013004:Somatostatin; D001839:Bombesin; D014975:Lutein