Biomedical subjects

Andrew V Schally

Publications and source records attributed to Andrew V Schally.

At least 19 recordsLinked to original sources

PubMed2006

Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxel.

We investigated the effect of antagonists of growth hormone-releasing hormone (GHRH) MZ-J-7-138 and JV-1-92 on H460 human non-small cell lung carcinoma (NSCLC) xenografted orthotopically into nude mice. Treatment with MZ-J-7-138 or JV-1-92 inhibited orthotopic growth of H460 NSCLC by 52-65% (P < 0.001) and was associated with a significant decrease in protein expression of K-Ras, cyclooxygenase-2 (Cox-2) and phospho-Akt (pAkt). In other experiments, treatment with MZ-J-7-138 or docetaxel reduced tumor volume of s.c. xenografted H460 human NSCLC by 30-36% (P < 0.01). The combination of MZ-J-7-138 and docetaxel resulted in a synergistic growth inhibition of H460 NSCLC xenografts of 63%. MZ-J-7-138 alone or in combination with docetaxel significantly reduced protein levels of K-Ras, Cox-2, and pAkt by 56-63%. Docetaxel given singly diminished the protein levels only of Cox-2 and did not affect K-Ras and pAkt. High-affinity binding sites, mRNA, and protein expression of pituitary GHRH receptors and its splice variant (SV) 1 were found in H460. H460 NSCLC cells contained GHRH peptide, and its growth was significantly inhibited in vitro by 10 microM MZ-J-7-138 (P < 0.001). Serum insulin-like growth factor 1 (IGF1) was not reduced by either GHRH antagonists. These findings suggest that antiproliferative effects of GHRH antagonists in H460 NSCLC are associated with down-regulation of K-Ras, Cox-2, and pAkt. In conclusion, GHRH antagonists in combination with docetaxel synergistically inhibit growth of H460 NSCLC and the expression of K-ras, Cox-2, and pAkt, which might abrogate the signal transduction pathways for cell growth stimulation and therapeutic resistance.

Alternative Splicing↗

PubMed2006

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

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.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Effects of combined long-term treatment with a growth hormone-releasing hormone analogue and a growth hormone secretagogue in the growth hormone-releasing hormone knock out mouse.

GH secretagogues (GHS) are synthetic ghrelin receptor agonists that stimulate GH secretion. It is not clear whether they act predominantly by stimulating the secretion of hypothalamic growth hormone-releasing hormone (GHRH), or directly on the somatotrope cells. In addition, it is not known whether combined treatment with GHRH and GHS has synergistic effects on growth. To address these questions, we used the GH-deficient GHRH knock out (GHRHKO) mouse model, which has severe somatotrope cell hypoplasia. We treated GHRHKO mice for 5 weeks (from week 1 to week 6 of age) with the GHRH analogue JI-38 alone, or in combination with a GHS (GHRP-2), and at the end of the treatment we examined their response to an acute stimulus with GHRP-2 or GHRP-2 plus JI-38. We used placebo-treated GHRHKO mice and animals heterozygous for the GHRHKO allele as controls. Animals treated with JI-38+GHRP-2 reached higher body length and weight than animals treated with JI-38 alone. All the animals receiving JI-38 (with or without GHRP-2) showed similar correction of somatotrope cell hypoplasia. None of the GHRHKO animals showed a serum GH response to the acute stimulation with GHRP-2 alone, while both treated groups responded to the combined test with JI-38 + GHRP-2. These data demonstrate that in GHRHKO mice, GHRP-2 has a growth-stimulating effect that augments the response induced by JI-38. In addition, the presence of GHRH seems necessary for the stimulation of GH secretion by GHRP-2.

Animals↗

PubMed2006

Lipopeptide antagonists of growth hormone-releasing hormone with improved antitumor activities.

Antagonists of growth hormone-releasing hormone (GHRH) synthesized previously inhibit proliferation of various human cancers, but derivatisation with fatty acids could enhance their clinical efficacy. We synthesized a series of antagonists of GHRH(1-29)NH(2) acylated at the N terminus with monocarboxylic or alpha,omega-dicarboxylic acids containing six to sixteen carbon atoms. These peptides are analogs of prior potent antagonists JV-1-36, JV-1-38, and JV-1-65 with phenylacetyl group at their N terminus. Several new analogs, including MZ-J-7-46 and MZ-J-7-30, more effectively inhibited GHRH-induced GH release in vitro in a superfused rat pituitary system than their parent compound JV-1-36 and had increased binding affinities to rat pituitary GHRH receptors, but they showed weaker inhibition of GH release in vivo than JV-1-36. All antagonists acylated with fatty acids containing 8-14 carbon atoms inhibited the proliferation of MiaPaCa-2 human pancreatic cancer cells in vitro better than JV-1-36 or JV-1-65. GHRH antagonist MZ-J-7-114 (5 mug/day) significantly suppressed the growth of PC-3 human androgen-independent prostate cancers xenografted into nude mice and reduced serum IGF-I levels, whereas antagonist JV-1-38 had no effect at the dose of 10 mug/day. GHRH antagonists including MZ-J-7-46 and MZ-J-7-114 acylated with octanoic acid and MZ-J-7-30 and MZ-J-7-110 acylated with 1,12-dodecanedicarboxylic acid represent relevant improvements over earlier antagonists. These and previous results suggest that this class of GHRH antagonists might be effective in the treatment of various cancers.

Animals↗

PubMed2006

Inhibition of human experimental prostate cancers by a targeted cytotoxic luteinizing hormone-releasing hormone analog AN-207.

BACKGROUND: Receptors for luteinizing hormone-releasing hormone (LHRH) on human prostate cancers can be used for targeted chemotherapy with cytotoxic analogs of LHRH, such as AN-207, which consists of superactive doxorubicin derivative 2-pyrrolino doxorubicin (AN-201) linked to carrier [D-Lys6] LHRH. METHODS: The effects of AN-207 and AN-201 were investigated in DU-145 androgen independent and LuCaP-35 androgen sensitive human prostate cancers xenografted into nude mice. Toxicity was evaluated by survival rates, changes in body weights, and leukocyte counts. LHRH receptors on DU-145 and LuCaP-35 tumors were evaluated by radioreceptor assays and RT-PCR. The effects on apoptosis and cell proliferation were investigated by histology and evaluation of apoptotic oncogenes Bcl-2 and Bax by Western Blot analysis. RESULTS: AN-207 inhibited growth of DU-145 tumors significantly by 75% (P < 0.01) and LuCaP-35 human prostate cancers by 80% (P < 0.01), and was less toxic than AN-201. Receptors for LHRH were expressed on DU-145 and LuCaP-35 tumors. Blockade of LHRH receptors with LHRH agonist Triptorelin nullified the effects of AN-207. Treatment with AN-207, but not with AN-201, decreased Bcl-2/Bax ratio in DU-145 tumors and Bcl-2 in LuCaP-35 tumors indicating an increase in apoptotic activity. AN-207, but not AN-201, decreased cell proliferation in both models. CONCLUSIONS: Targeted chemotherapy with AN-207 could be considered for treatment of advanced prostate cancer.

Androgens↗

PubMed2006

Targeted chemotherapy with cytotoxic bombesin analogue AN-215 inhibits growth of experimental human prostate cancers.

We developed a powerful cytotoxic analogue of bombesin AN-215, in which the bombesin (BN)-like carrier peptide is conjugated to 2-pyrrolino doxorubicin (AN-201). Human prostate cancers express high levels of receptors for BN/gastrin releasing peptide (GRP) that can be used for targeted chemotherapy. The effects of targeted chemotherapy with cytotoxic BN analogue AN-215 were evaluated in nude mice bearing subcutaneous xenografts of DU-145, LuCaP-35, MDA-PCa-2b and intraosseous implants of C4-2 human prostate cancers. Intraosseous growth of C4-2 tumors was monitored by serum PSA. BN/GRP receptors were evaluated by 125I-[Tyr4]BN binding assays and RT-PCR. The effects of AN-215 on apoptosis and cell proliferation were followed by histology, and the expression of Bcl-2 and Bax protein was determined by Western blot analysis. Targeted analog AN-215 significantly inhibited growth of subcutaneously implanted DU-145, LuCaP-35 and MDA-PCa-2b prostate cancers by 81% to 91% compared to controls, while cytotoxic radical AN-201 was less effective and more toxic. Serum PSA levels of mice bearing intraosseous C4-2 prostate tumors were significantly reduced. In LuCaP-35 tumors administration of BN antagonist RC-3095 prior to AN-215 blocked the receptors for BN/GRP and inhibited the effects of AN-215. High affinity receptors for BN/GRP and their m-RNA were detected on membranes of all 4 tumor models. Therapy with AN-215, but not with AN-201, decreased the ratio of Bcl-2/Bax in DU-145 and the expression of antiapoptotic Bcl-2 in LuCaP-35 tumors. The presence of BN/GRP receptors on primary and metastatic prostate cancers makes possible targeted chemotherapy with AN-215 for the treatment of this malignancy.

Animals↗

PubMed2006

Antagonists of growth hormone-releasing hormone in oncology.

The development of antagonists of growth hormone (GH) - releasing hormone (GH-RH) is reviewed. GH-RH antagonists bind with a high affinity to pituitary receptors for GH-RH and inhibit the release of GH in vitro and in vivo. The main applications of GH-RH antagonists would be for tumor therapy. The antitumor effects of GH-RH antagonists are exerted in part indirectly through the inhibition of the secretion of pituitary GH and the reduction in the levels of hepatic insulin like growth factor (IGF-I). However, principal effects of the GH-RH antagonists are exerted directly on tumors. Antagonists of GH-RH inhibit the proliferation of various cancer cell lines in vitro and suppress in vivo the levels and the expression of mRNA for IGF-I and IGF-II in tumors. In many human cancers, the effects of GH-RH antagonists appear to be due to the blockade of the action of tumoral GH-RH. GH-RH ligand is present in various human cancers indicating that it may be an autocrine/paracrine growth factor. Splice variants (SVs) of GH-RH receptors and pituitary type of GH-RH receptors that might mediate effects of tumoral GH-RH and of GH-RH antagonists were demonstrated in many human cancers. This suggests the presence of a stimulatory loop based on GH-RH and SVs or pituitary type of GH-RH receptors in diverse tumors. It was shown that GH-RH antagonists inhibited the growth of various human cancer lines xenografted into nude mice including mammary, ovarian, endometrial and prostate cancers, small cell lung carcinomas (SCLC) and non-SCLC, renal, pancreatic, gastric and colorectal carcinomas, malignant gliomas, osteosarcomas and Non-Hodgkin's lymphomas. Further development of GH-RH antagonists should lead to potential therapeutic agents for various cancers.

Animals↗

PubMed2006

Effective therapy of experimental human malignant melanomas with a targeted cytotoxic somatostatin analogue without induction of multi-drug resistance proteins.

Malignant melanomas are characterized by a high intrinsic resistance to chemotherapy. Multiple drug resistance (MDR) can be mediated by transport proteins such as MDR-1, multidrug resistance-associated protein (MRP) or lung resistance protein (LRP). The cytotoxic analogue of somatostatin AN-238 consisting of 2-pyrrolinodoxorubicin (AN-201) linked to a somatostatin analogue RC-121 binds to receptors for somatostatin and is targeted to tumors expressing these receptors. We evaluated the expression of somatostatin receptors on human malignant melanoma tumor lines MRI-H255 and MRI-H187 and examined the effects of the targeted analogue AN-238 and its cytotoxic radical AN-201 on growth of these tumors in nude mice. We also studied the effects of AN-238 and AN-201 on the expression of MDR-1, MRP-1 and LRP by real-time PCR. AN-238 inhibited the growth of MRI-H255 and MRI-H187 tumors while AN-201 was ineffective. Blockade of somatostatin receptors by somatostatin analogue RC-121 abolished the effects of AN-238. Targeted therapy with AN-238 did not produce an induction of mRNA of MDR-1, MRP-1 or LRP. Our findings show that targeted chemotherapy with cytotoxic somatostatin analogue AN-238 inhibits the growth of malignant melanomas. AN-238 could provide a novel treatment approach for advanced malignant melanomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Elevated levels of circulating insulin-like growth factor-I, IGF-binding globulin-3 and testosterone predict hormone-dependent breast cancer in postmenopausal women: a case-control study.

There is increasing evidence that different types of breast cancers are related to distinct risk factors. We analyzed the risk of breast cancer with respect to circulating insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-3, 17beta-estradiol, estrone, testosterone, androstenedione and sex hormone-binding globulin (SHBG), taking into consideration the characteristics of the tumors. Plasma hormone levels of 102 postmenopausal patients with breast cancer detected by mammography screening, and 102 matched controls were analyzed in relation to the histological type, the status of the estrogen receptor (ER), the progesterone receptor (PR) and the HER2 in the tumors. Significant positive associations were revealed between the IGF-I concentration and the overall risk of breast cancer (OR=3.1, 95% CI: 1.5-6.2), ER+PR+ breast cancer (OR=2.4, 95% CI: 1.1-5.4) and ER+PR- breast cancer (OR=4.3, 95% CI: 1.2-14.3) when the highest and the lowest ranges of IGF-I were compared. Significant associations were also found between the highest and the lowest quartiles of testosterone, resulting in OR=4.1 (95% CI: 1.8-9.4) for the risks of breast cancer and OR=5.8 (96% CI: 2.1-16.2) of ER+PR+ breast cancer. A synergy was seen between IGF-I and testosterone levels. When both plasma IGF-I and testosterone were in the highest quartile ranges, an OR=26.4 (95% CI: 1.6-426.5, p=0.021) was computed for breast cancer overall. No significant synergistic effects could be demonstrated with other parameters. There were significant, 2.5-fold (95% CI: 1.2-5.6), and 16-fold (95% CI: 2.0-133.5) increases in the overall risks of breast cancer and of ER+PR- breast cancer, respectively, when the highest and the lowest quartiles of IGFBP-3 were compared. No associations were found between any of the hormones and the risk of ER-PR- tumors. The increased prevalence of ER+ breast cancers in patients with higher levels of IGF-I, IGFBP-3 or testosterone implicate these hormones in the etiology of hormone-dependent breast cancer. Additional analyses specific for breast cancer subtypes may shed light on the value of hormone determinations for tailored chemoprevention.

Aged↗

PubMed2006

Characterization of receptors for growth hormone-releasing hormone in human osteosarcomas and Ewing's sarcomas.

Antagonists of growth hormone-releasing hormone (GH-RH) inhibit growth of various human cancers including osteosarcomas and Ewing's sarcomas, xenografted into nude mice or cultured in vitro. The antiproliferative effect of GH-RH antagonists could be mediated, in part, through the splice variants (SVs) of receptors for GH-RH which have been found in several human cancers and cancer cell lines. In this study we investigated the expression of SVs of GH-RH receptors and the binding characteristics of these receptor isoforms in MNNG/HOS human osteosarcoma and SK-ES-1 human Ewing's sarcoma grown in nude mice. RT-PCR revealed the presence of mRNA for SVs of GH-RH receptors in both human malignant bone cancer models. Using ligand competition assays with 125I-labeled GH-RH antagonist JV-1-42, we demonstrated in MNNG/HOS and SK-ES-1 tumors the presence of specific high affinity binding sites for GH-RH (Kd=5.83 nM and Kd=2.76 nM) with a maximal binding capacity (Bmax) of 552.1 fmol/mg protein and 371.9 fmol/mg protein, respectively. We also investigated the effect of GH-RH antagonist JV-1-38, administered s.c. at a dose of 20 microg twice daily for 4 weeks on the gene expression, affinity and concentration of receptors for GH-RH in MNNG/HOS human osteosarcomas xenografted into nude mice. Treatment with JV-1-38 did not affect the expression and binding characteristics of GH-RH receptors. High affinity binding of JV-1-38 to GH-RH receptors on MNNG/HOS tumors was characterized by an IC50 value of 1.04 nM. The presence of GH-RH receptors in human bone tumors provides a rationale for new approaches to the therapy of this malignancy based on GH-RH antagonists.

Animals↗

PubMed2005

The expression of the pituitary growth hormone-releasing hormone receptor and its splice variants in normal and neoplastic human tissues.

Various attempts to detect human pituitary growth hormone-releasing hormone receptor (pGHRH-R) in neoplastic extrapituitary tissues have thus far failed. Recently, four splice variants (SVs) of GHRH-R have been described, of which SV1 has the highest structural homology to pGHRH-R and likely plays a role in tumor growth. The aim of this study was to reinvestigate whether human tumors and normal human extrapituitary tissues express the pGHRH-R and to corroborate our previous findings on its SVs. Thus, we developed a real-time PCR method for the detection of the mRNA for the pGHRH-R, its SVs, and the GHRH peptide. Using real-time PCR, Western blotting, and radioligand-binding assays, we detected the mRNA for pGHRH-R and pGHRH-R protein in various human cancer cell lines grown in nude mice and in surgical specimens of human lung cancers. The expression of mRNA for SVs of pGHRH-R and GHRH was likewise found in xenografts of human non-Hodgkin's lymphomas, pancreatic cancer, glioblastoma, small-cell lung carcinomas, and in human nonmalignant prostate, liver, lung, kidney, and pituitary. Western blots showed that these normal and malignant human tissues contain SV1 protein and immunoreactive GHRH. Our results demonstrate that some normal human tissues and tumors express mRNA and protein for the pGHRH-R and its splice variants. These findings confirm and extend the concept that GHRH and its receptors play an important role in the pathophysiology of human cancers.

Alternative Splicing↗

PubMed2005

Targeted chemotherapy with cytotoxic bombesin analogue AN-215 can overcome chemoresistance in experimental renal cell carcinomas.

BACKGROUND: Multidrug resistance (MDR) mediated by membrane transporters, such as P-glycoprotein (MDR-1) and MDR-associated protein (MRP), remains a challenge in the therapy of renal cell carcinoma (RCC). Chemotherapy targeted to hormone receptors may provide a new approach to overcome chemoresistance. The cytotoxic analogue of bombesin/gastrin-releasing peptide (GRP), AN-215, consists of a superactive derivative of doxorubicin, AN-201, which is linked to a bombesin analogue carrier: RC-3094. METHODS: The authors examined the expression of bombesin/GRP receptors in 3 human RCC cell lines (A-498, ACHN. and 786-0) by using reverse-transcriptase-polymerase chain reaction (RT-PCR) analysis and radioligand-binding assays. They also evaluated the effects of AN-215 and its cytotoxic radical AN-201 in the same RCC models in vivo, and they studied the effects of AN-215 and AN-201 on the expression levels of MDR-1 and subtype 1 of MRP (MRP-1) by using real-time PCR. RESULTS: A N-215 significantly (P < 0.05) inhibited the growth of A-498, ACHN, and 786-0 RCC xenografted into nude mice by 59.2-67.6%, whereas the cytotoxic radical AN-201 alone had no significant antitumor effects. The efficacy of AN-215 was independent of the expression patterns of MDR-1 and MRP-1 in these RCC cell lines. The induction of MDR-1 by AN-215 was similar (Experiment 2) or weaker (Experiment 1) compared with AN-201. Both AN-215 and AN-201 caused only a minor induction of MRP-1. CONCLUSIONS: The current findings indicated that targeted chemotherapy with cytotoxic bombesin/GRP analogue AN-215 can inhibit the growth of RCC, providing a new treatment modality for patients with advanced RCC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Targeted therapy with a cytotoxic somatostatin analog, AN-238, inhibits growth of human experimental endometrial carcinomas expressing multidrug resistance protein MDR-1.

BACKGROUND: Chemoresistance mediated by membrane transporters such as multidrug resistance (MDR-1) glycoprotein remains a challenge in the chemotherapy treatment of advanced or recurrent endometrial carcinoma. Targeted chemotherapy might overcome this resistance. The cytotoxic somatostatin (SST) analog, AN-238, consists of a superactive derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201), linked to the SST analog carrier, RC-121. This conjugate binds strongly to SST receptor subtypes (sst) 2a (sst2(a)) and 5 (sst(5)) and can be targeted to tumors that express these receptors. METHODS: The presence of sst2(a) and sst(5) was determined in 3 human endometrial carcinoma cell lines (HEC-1A, RL-95-2, and AN3CA). Nude mice bearing xenografts of these cancers were treated with AN-238 and its radical, AN-201. The antitumor effects and toxicity were compared. The authors studied the effects of AN-238 and AN-201 on the expression levels of MDR-1, multidrug resistance related protein (MRP-1), and breast carcinoma resistance protein (BCRP) by real-time polymerase chain reaction. RESULTS: The authors demonstrated the presence of mRNA and receptor protein for sst(2a) and sst(5) on HEC-1A, RL-95-2, and AN3CA tumors. AN-238 significantly (P < 0.05) inhibited the growth of these tumors, whereas AN-201 had no effect. Blockade of SST receptors nullified the effects of AN-238. In all 3 endometrial carcinoma lines, AN-238 caused a weaker induction of MDR-1 than AN-201. No major induction of MRP-1 and BCRP occurred after treatment with AN-238 or AN-201. CONCLUSIONS: Targeted chemotherapy with the cytotoxic SST analog, AN-238, inhibited powerfully the growth of endometrial carcinoma, which express SST receptors, regardless of their expression level of MDR-1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Antagonists of growth hormone releasing hormone and bombesin inhibit the expression of EGF/HER receptor family in H-69 small cell lung carcinoma.

Effects of in vivo treatment with antagonists of growth hormone-releasing hormone (GHRH), JV-1-65 and MZ-J-7-110, and bombesin/gastrin-releasing peptide antagonist RC-3940-II, on the EGF receptor (EGFR) family, were investigated in H-69 SCLC. Tumors were analyzed by RT-PCR, immunoblotting and binding assays. Treatment with these analogs reduced the binding capacity of EGFR by 18-64%, and inhibited the mRNA expression for EGFR, HER-2 and -3 by 27-75.4, 17-26.3, and 13.8-46.6%, respectively. The antagonists also decreased the protein levels for EGFR by 21-34%, HER-2 by 36-68% and HER-3 by 43-49%. This is the first demonstration that antiproliferative effects of GHRH antagonists are associated with a downregulation of EGF/HER receptors.

Blotting, Western↗

PubMed2005

Antagonists of growth hormone-releasing hormone cross the blood-brain barrier: a potential applicability to treatment of brain tumors.

Hypothalamic growth hormone (GH)-releasing hormone (GHRH) stimulates the synthesis and release of GH from the pituitary gland. GHRH and its mRNA are also found in human cancers of the breast, ovary, prostate, lung, and other tumors, suggesting that GHRH is also a tumor growth factor. Various studies show that GHRH antagonists have antiproliferative effects in many tumor models; however, glioblastomas were examined only recently. Previous studies have demonstrated that s.c. administration of GHRH antagonist (JV-1-36) inhibited growth of s.c. U-87MG human glioblastomas and increased survival of nude mice with orthotopic implants of glioblastomas. Although treatment with JV-1-36 reduced tumorigenicity, it is not known whether peripherally administered GHRH antagonists can cross the blood-brain barrier. Brain endothelial cells joined by tight junctions form the blood-brain barrier, a "barrier" between the general circulation and the CNS. In this study, we administered a GHRH antagonist (JV-1-42) and showed that, after i.v. injection, iodinated JV-1-42 (131I-JV-1-42) enters the brain intact at a rate of 0.8514 mocrol/g per min with a serum half-life of 12.2 min. A one-site binding hyperbolic model indicated that the maximal percent of i.v. dose taken up per gram of brain was 0.41%. Coinjection of unlabeled JV-1-42 indicated that the transport from blood to brain is not saturable; however, transport from brain to blood is saturable and involves P-glycoprotein. Taken together, these results demonstrate that i.v.-administered 131I-JV-1-42 readily crosses the blood-brain barrier and accumulates in the brain. This finding indicates that GHRH antagonists could provide a potential treatment for malignant glioblastomas.

Animals↗

PubMed2005

Antagonists of growth hormone releasing hormone (GHRH) and of bombesin/gastrin releasing peptide (BN/GRP) suppress the expression of VEGF, bFGF, and receptors of the EGF/HER family in PC-3 and DU-145 human androgen-independent prostate cancers.

BACKGROUND: Antagonists of growth hormone releasing hormone (GHRH) as well as antagonists of bombesin/gastrin releasing peptide (BN/GRP) inhibit the growth of various malignancies (cancers) including prostate cancer. METHODS: We investigated the effects of GHRH antagonists MZ-J-7-118 and RC-J-29-18, BN/GRP antagonists RC-3940-II and RC-3940-Et and the combination of MZ-J-7-118 and RC-3940-II on the growth of PC-3 and DU-145 human androgen independent prostate cancers xenografted s.c. into nude mice. To elucidate the mechanisms of action of these analogs, growth factors like IGF-II (insulin-like growth factor-II), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and epidermal growth factor receptor/human epidermal growth factor receptor (EGF-R/HER) family were measured in tumors as well as IGF-I in serum. RESULTS: Antagonists of GHRH and BN/GRP alone or in combination significantly inhibited growth of PC-3 and DU-145 tumors, the greatest inhibition of tumor volume being achieved by combination of MZ-J-7-118 (5 microg/day) and RC-3940-II (10 microg/day). BN/GRP and GHRH antagonists and their combination also decreased the expression of VEGF significantly in PC-3 and non-significantly in DU-145, as measured by radioimmunoassay for VEGF protein and RT-PCR for mRNA levels of VEGF. GHRH and BN/GRP antagonists reduced bFGF concentrations and the maximal binding capacity of EGF receptors, and their mRNA levels in PC-3 and DU-145 tumors. mRNA levels for HER-2 and -3 were also diminished in PC-3 tumors by GHRH and BN/GRP antagonists. No changes in HER-4 were found after treatment. Serum IGF-I and tumoral IGF-II levels were not affected by the analogs. CONCLUSIONS: BN/GRP and GHRH antagonists inhibit growth of PC-3 and DU-145 prostate cancers by suppressing the expression of tumoral growth factors such as VEGF and bFGF as well as the receptors for EGF and related HER-2 and -3. Additive effects on tumor inhibition (TI) in vivo, but not on VEGF, bFGF, or members of the EGF/HER receptor family, can be achieved by the joint administration of both classes of analogs.

Animals↗

PubMed2005

Receptors for luteinizing hormone releasing hormone expressed on human renal cell carcinomas can be used for targeted chemotherapy with cytotoxic luteinizing hormone releasing hormone analogues.

PURPOSE: To determine the expression of luteinizing hormone releasing hormone (LHRH) receptors in specimens and cell lines of human renal cell carcinoma (RCC) and to evaluate the antitumor efficacy of targeted therapy with a cytotoxic analogue of LHRH, AN-207, in vivo. AN-207, consisting of [D-Lys(6)] LHRH linked to a cytotoxic radical, 2-pyrrolinodoxorubicin (AN-201), binds with high affinity to LHRH receptors and can be targeted to tumors expressing these receptors. EXPERIMENTAL DESIGN: The expression of LHRH receptors was investigated in 28 surgically removed specimens of human renal cell carcinoma (RCC) by immunohistochemistry and in three human RCC cell lines A-498, ACHN, and 786-0 by radioreceptor assays, Western immunoblotting, and reverse transcription-PCR analysis. Antitumor efficacy of AN-207 was examined in experimental models of these cell lines. RESULTS: Positive staining for LHRH receptors was found in all (28 of 28) of the examined human RCC specimens. mRNA for LHRH receptor, receptor protein, and LHRH binding sites were detected in all three cell lines. AN-207 significantly (P < 0.05) inhibited the growth of A-498, ACHN, and 786-0 xenografts in vivo producing a 67.8% to 73.8% decrease in tumor volume and a 62.2% to 77.3% reduction in tumor weight. Nontargeted cytotoxic radical AN-201 had no significant antitumor effects. Blockade of LHRH receptors by an excess of LHRH agonist Decapeptyl suppressed tumor inhibitory effects of AN-207. CONCLUSIONS: Our findings indicate that LHRH receptors are expressed in human RCC specimens and can be used for targeted chemotherapy with cytotoxic LHRH analogues.

Animals↗

PubMed2005

Targeting of cytotoxic luteinizing hormone-releasing hormone analogs to breast, ovarian, endometrial, and prostate cancers.

Targeted chemotherapy is a modern approach aimed at increasing the efficacy of systemic chemotherapy and reducing its side effects. The peptide receptors expressed primarily on cancerous cells can serve as targets for a selective destruction of malignant tumors. Binding sites for LHRH (now known in genome and microarray databases as GNRH1), were found on 52% of human breast cancers, about 80% of human ovarian and endometrial cancers, and 86% of human prostatic carcinoma specimens. Because LHRH receptors are not expressed on most normal tissues, they represent a specific target for cancer chemotherapy with antineoplastic agents linked to an LHRH vector molecule. To test the efficacy of targeted chemotherapy based on LHRH analogs, we recently developed a cytotoxic analog of LHRH, designated AN-152, which consists of [D-Lys6]LHRH covalently linked to one of the most widely used chemotherapeutic agents, doxorubicin (DOX). In addition, we designed and synthesized a highly active derivative of DOX, 2-pyrrolino-DOX (AN-201), which is 500-1000 times more potent than DOX in vitro. AN-201 is active against tumors resistant to DOX, and noncardiotoxic. As in the case of DOX, AN-201 was coupled to carrier peptide [D-Lys6]LHRH to form a superactive targeted cytotoxic LHRH analog, AN-207. Both AN-152 and AN-207 can effectively inhibit the growth of LHRH receptor-positive human breast, ovarian, endometrial, and prostate cancers xenografted into nude mice. DOX-containing cytotoxic LHRH analog AN-152 is scheduled for clinical phase I/IIa trials in patients with advanced ovarian and breast cancers in 2005.

Animals↗