Specific receptors for luteinizing hormone-releasing hormone (LH-RH), somatostatin, bombesin, and other peptides are found on various cancers. We review the development of cytotoxic analogs of LH-RH, somatostatin, and bombesin/gastrin releasing peptide (GRP) designed for targeting chemotherapy to peptide receptors on various cancers. Cytotoxic analogs of LH-RH, AN-152 and AN-207, containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201), respectively, target LH-RH receptors and may be used for the treatment of prostatic and urinary bladder (urothelial), breast, ovarian and endometrial cancers, non-Hodgkin's lymphomas, melanomas, and renal cell carcinomas. DOX and AN-201 have also been incorporated into the cytotoxic analogs of somatostatin, AN-162 and AN-238, respectively, which are targeted to receptors for somatostatin in prostatic, mammary, ovarian, gastric, renal, colorectal and pancreatic cancers, non-Hodgkin's lymphomas, as well as glioblastomas and lung cancers. They are found to suppress the growth of these tumors and their metastases. A cytotoxic analog of bombesin/GRP, AN-215, containing 2-pyrrolino-Dox, has also been synthesized and shown to inhibit growth of various human cancer lines expressing receptors for bombesin/GRP. The toxicity, pharmacokinetics and maximum tolerated doses of AN-152 were assessed in a phase I clinical trial in women with ovarian or endometrial cancer. Disease stabilization and objective responses were found. Analog AN-152 is now in phase II clinical trials. Phase I/II studies with AN-152 in men with hormone-independent relapsed prostate cancer and patients with pancreatic and bladder cancers are pending. Targeted cytotoxic peptide analogs could provide a more efficacious and less toxic therapy for various cancers.

01 Apr 2008·Anti-Cancer DrugsQ4 · MEDICINE

Therapy of experimental hepatic cancers with cytotoxic peptide analogs targeted to receptors for luteinizing hormone-releasing hormone, somatostatin or bombesin

Q4 · MEDICINE

Article

Author: Karoly Szepeshazi ; Stephan Seitz ; Andrew V. Schally ; Andrea Treszl ; Gabor Halmos

As there is no effective systemic therapy for advanced hepatocellular carcinoma (HCC), we investigated the presence of receptors for somatostatin, bombesin and luteinizing hormone-releasing hormone (LHRH) in SK-Hep-1 human hepatic carcinoma and the effects of cytotoxic analogs of somatostatin (AN-238), bombesin (AN-215) and LHRH (AN-207) on the growth of this tumor. Nude mice bearing SK-Hep-1 HCCs were treated with AN-238, AN-215, AN-207 and their combination, or cytotoxic radical 2-pyrrolinodoxorubicin (AN-201). Tumor growth reduction was determined and cell proliferation characteristics and apoptosis were studied by histologic analysis. The expression of receptors for somatostatin, bombesin and LHRH was investigated by radioreceptor assays and immunohistochemistry. High-affinity binding sites for somatostatin, bombesin and LHRH were detected in SK-Hep-1 cancers. All three cytotoxic peptide analogs inhibited growth of SK-Hep-1 tumors and decreased the cell proliferation rate. Combination therapy with two or three cytotoxic analogs resulted in the strongest tumor inhibition. Receptors for somatostatin, bombesin and LHRH are expressed in SK-Hep-1 human HCC. Cytotoxic peptide analogs targeted to these receptors inhibit growth of this tumor. Targeting to multiple receptors enhances the efficacy of therapy. The results of our study encourage additional experimental investigations to permit the introduction of these cytotoxic analogs into clinical trials.

05 Jul 2006·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Therapy of ovarian cancers with targeted cytotoxic analogs of bombesin, somatostatin, and luteinizing hormone-releasing hormone and their combinations

Q1 · CROSS-FIELD

Article

Author: Buchholz, Stefan ; Halmos, Gabor ; Heinrich, Elmar ; Koester, Frank ; Baker, Benjamin ; Schally, Andrew V. ; Keller, Gunhild ; Hohla, Florian ; Engel, Jörg B.

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Preclinical	US	Tulane University School of Medicine	-
Solid tumor	Preclinical	US	Tulane University School of Medicine	-
Solid tumor	Preclinical	US	AEterna Zentaris GmbH	-
Solid tumor	Preclinical	US	AEterna Zentaris GmbH	-

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