14 research outputs found
Luteinizing hormoneâreleasing hormone (LHâRH) antagonist Cetrorelix inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of IGF-II in tumors
In previous studies, we showed that LHâRH antagonist Cetrorelix inhibits the growth of DU-145 and PC-3 human androgen-independent prostate cancers in nude mice. To investigate the mechanisms involved, we treated male nude mice bearing xenografts of DU-145 human androgen-independent prostate cancer with Cetrorelix at a dose of 100 ÎŒg/animal subcutaneously (s.c.) once a day. Tumor growth, serum and tumor levels of IGF-I and -II as well as the mRNA expression of IGF-I and -II in tumors were evaluated. After 8 weeks of treatment, final volume and weight of DU-145 tumors in mice treated with Cetrorelix were significantly decreased compared with controls and serum IGF-1 showed a significant reduction. Therapy with Cetrorelix also reduced by 84% the levels of IGF-II in DU-145 tumor tissue compared with controls, but did not affect the concentration of IGF-I. RTâPCR analyses revealed a high expression of mRNA for IGF-II, but not for IGF-I in DU-145 tumors. Treatment with Cetrorelix decreased the expression of IGF-II mRNA by 78% (
p<0.01) as compared with controls. Our study indicates that LHâRH antagonist Cetrorelix may inhibit the growth of DU-145 human androgen-independent prostate cancers by decreasing the production and mRNA expression of IGF-II by the tumor tissue. This also suggests that LH-RH antagonist Cetrorelix could interfere with the signal transduction pathways involving IGF-II, leading to tumor growth inhibition
Growth hormone-releasing hormone antagonist MZ-5-156 inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of insulin-like growth factor II in tumors
Insulin-like growth factors I and II (IGF-I and -II) are potent mitogens for various cancers, including carcinoma of the prostate. In several experimental cancers, treatment with antagonists of growth hormone-releasing hormone (GH-RH) produces a reduction in IGF-I and -II, concomitant to inhibition of tumor growth. To investigate the mechanisms involved, we treated male nude mice bearing xenografts of DU-145 human androgen-independent prostate cancer for 8 weeks with potent GH-RH antagonist MZ-5-156 at a dose of 20 ÎŒg/animal s.c. twice a day. Tumor growth, serum and tumor levels of IGF-I and -II, and the mRNA expression of IGF-I and -II in tumors were evaluated. After 8 weeks of therapy, final volume and weight of DU-145 tumors in mice treated with MZ-5-156 were significantly (P < 0.01) decreased compared with controls, and serum IGF-I showed a significant reduction. Treatment of nude mice bearing DU-145 xenografts with MZ-5-156 also significantly (P < 0.01) diminished by 77% the levels of IGF-II in tumor tissue compared with controls, but did not affect the concentration of IGF-I. Reverse transcriptionâPCR analyses revealed a high expression of IGF-II mRNA in DU-145 tumors. Treatment with GH-RH antagonist MZ-5-156 decreased the expression of IGF-II mRNA by 58% (P < 0.01) as compared with controls. Our work suggests that GH-RH antagonist MZ-5-156 may inhibit the growth of DU-145 human androgen-independent prostate cancers through a reduction in the production and mRNA expression of IGF-II by the tumor tissue. These findings extend our observations on the mechanism of action of GH-RH antagonists and may explain how GH-RH antagonists inhibit tumor growth
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Cytotoxic analogs of luteinizing hormone-releasing hormone bind with high affinity to human breast cancers
Recently, we developed two new cytotoxic analogs of luteinizing hormone-releasing hormone (LH-RH), AN-152 in which doxorubicin (DOX) is linked to [D-Lys
6]LH-RH, and AN-207 which consists of 2-pyrrolino-DOX coupled to [D-Lys
6]LH-RH. In this study, we examined binding of AN-152 and AN-207 to membranes of human breast cancer specimens and MCF-7 and MDA-MB-231 human breast cancer lines. Both cytotoxic analogs displayed IC
50 values in the nanomolar concentration range (IC
50=2â13 nM). Using radioligand binding studies, we characterized the receptors for LH-RH on membranes of breast cancers. In addition, the expression of mRNA for LH-RH receptors in MCF-7 and MDA-MB-231 cell lines was demonstrated by reverse transcriptionâpolymerase chain reaction (RTâPCR). These highly active cytotoxic analogs of LH-RH have been designed as targeted chemotherapeutic agents for the treatment of various cancers expressing receptors for LH-RH
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Bombesin/gastrinâreleasing peptide antagonists RCâ3095 and RCâ3940âII inhibit tumor growth and decrease the levels and mRNA expression of epidermal growth factor receptors in Hâ69 small cell lung carcinoma
BACKGROUND
Antagonists of bombesin/gastrinâreleasing peptide (BN/GRP) have been developed to block the autocrine stimulatory effect of BN/GRP on tumors such as small cell lung carcinoma (SCLC). Although several studies have addressed the intracellular events that follow the formation of the receptorâligand complex, the mechanism of action of BN/GRP antagonists remains unclear.
METHODS
In this study the authors investigated the effect of synthetic BN/GRP antagonists RCâ3095 and RCâ3940âII on tumor growth and the expression of epidermal growth factor receptors (EGFâR) in Hâ69 SCLC. Athymic nude mice xenografted with Hâ69 SCLC were treated subcutaneously for 5 weeks with RCâ3095 and RCâ3940âII at the dose of 10 ÎŒg/animal/day.
RESULTS
RCâ3095 decreased tumor volume by approximately 50% (P < 0.05) and RCâ3940âII by 70â60% (P < 0.01). Tumor burden also was significantly decreased in the groups treated with RCâ3095 and RCâ3940âII. Receptor analyses demonstrated high affinity binding sites for BN/GRP and EGF on the untreated Hâ69 SCLC tumors. After treatment with RCâ3095 and RCâ3940âII, the concentration of receptors for BN/GRP was decreased by 29.0% and 36.5%, respectively (both, P < 0.01) compared with controls, and EGFâR levels were reduced by 62.3% and 63.0%, respectively (both, P < 0.01). Reverse transcriptaseâpolymerase chain reaction and Southern blot analyses revealed that the levels of mRNA for EGFâR in tumors were lowered by 31% (P < 0.05) and 43% (P < 0.01), respectively, after treatment with RCâ3095 and RCâ3940âII.
CONCLUSIONS
This study indicates that the inhibition of growth of Hâ69 SCLC by BN/GRP antagonists RCâ3095 and RCâ3940âII is accompanied by a marked decrease in the levels and mRNA expression of EGFâR. Cancer 1998;83:1335â1343. © 1998 American Cancer Society.
Bombesin antagonists RCâ3095 and RCâ3940âII effectively inhibited growth of Hâ69 small cell lung carcinoma in nude mice and reduced the level and mRNA expression of epidermal growth factor receptors on tumor membranes. These peptide analogs should be considered for the treatment of small cell lung carcinoma
A single in vivo administration of bombesin antagonist RC-3095 reduces the levels and mRNA expression of epidermal growth factor receptors in MXT mouse mammaryâcancers
Epidermal growth factor (EGF) and its receptors (EGFR) play important roles in tumorigenesis. In various experimental cancers, treatment with antagonists of bombesin/gastrin-releasing peptide (BN/GRP) produces a reduction in EGFRs, concomitant to inhibition of tumor growth. To investigate the mechanisms involved, we monitored concentrations of BN/GRP antagonist RC-3095 in serum of mice, rats, and hamsters given a single subcutaneous or intravenous injection of this analog. In parallel studies, we measured levels and mRNA expression of EGFRs in estrogen-dependent and independent MXT mouse mammary cancers, following a single subcutaneous administration of RC-3095 to tumor-bearing mice. Peak values of RC-3095 in serum were detected 2 min after intravenous or 15 min after subcutaneous injection. The levels of RC-3095 declined rapidly and became undetectable after 3â5 hr. In the estrogen-dependent MXT tumors, the concentration of EGF receptors was reduced by about 60% 6 hr following injection and returned to original level after 24 hr. Levels of mRNA for EGFR fell parallel with the receptor number and were nearly normal after 24 hr. In the hormone-independent MXT cancers, the number of EGFRs decreased progressively, becoming undetectable 6 hr after injection of RC-3095, and returned to normal values at 24 hr, but EGFR mRNA levels remained lower for 48 hr. Thus, in spite of rapid elimination from serum, BN/GRP antagonist RC-3095 can induce a prolonged decrease in levels and mRNA expression of EGFRs. These findings may explain how single daily injections of BN/GRP antagonists can maintain tumor growth inhibition