Potentiation of mammary cancer inhibition by combination of antagonists of growth hormone-releasing hormone with docetaxel

被引:40
作者
Buchholz, Stefan
Schally, Andrew V.
Engel, Joerg B.
Hohla, Florian
Heinrich, Elmar
Koester, Frank
Varga, Jozsef L.
Halmos, Gabor
机构
[1] Vet Adm Med Ctr, Miami, FL 33125 USA
[2] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA
[3] Univ Regensburg, Klin & Poliklin Frauenheilkunde & Geburtshilfe, D-93051 Regensburg, Germany
[4] S Florida Vet Affairs Fdn Res & Educ, Vet Affairs Med Ctr, Miami, FL 33125 USA
[5] Univ Wurzburg, Frauenklin, D-97080 Wurzburg, Germany
[6] Univ Miami, Miller Sch Med, Miami, FL 33101 USA
[7] Hosp Oberndorf, Dept Internal Med, A-5100 Oberndorf, Austria
关键词
breast cancer; cancer therapy; chemotherapeutic agents; growth hormone-releasing hormone receptors;
D O I
10.1073/pnas.0610860104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Antagonists of growth hormone-releasing hormone (GHRIH) are being developed for the treatment of various cancers. In this study, we investigated the effectiveness of treatment with GHRH antagonist JMR-132 alone and in combination with docetaxel chemotherapy in nude mice bearing MX-1 human breast cancers. Specific high-affinity binding sites for GHRH were found on MX-1 tumor membranes using ligand competition assays with I-125-labeled GHRH antagonist JV-1-42. JMR-132 displaced radiolabeled JV-1-42 with an IC50 of 0.14 nM, indicating a high affinity of JMR-132 to GHRH receptors. Treatment of nude mice bearing xenografts of MX-1 with JMR-132 at 10 mu g per day s.c. for 22 days significantly (P < 0.05) inhibited tumor volume by 62.9% and tumor weight by 47.8%. Docetaxel given twice at a dose of 20 mg/kg i.p. significantly reduced tumor volume and weight by 74.1% and 58.6%, respectively. Combination treatment with JMR-132 (10 tLg/day) and docetaxel (20 mg/kg i.p.) led to growth arrest of most tumors as shown by an inhibition of tumor volume and weight by 97.7% and 95.6%, respectively (P < 0.001). Because no vital cancer cells were detected in some of the excised tumors, a total regression of the tumors was achieved in some cases. Treatment with JMR-132 also strongly reduced the concentration of EGF receptors in MX-1 tumors. Our results demonstrate that GHRIH antagonists might provide a therapy for breast cancer and could be combined with clocetaxel chemotherapy to enhance the efficacy of treatment.
引用
收藏
页码:1943 / 1946
页数:4
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