Spatially resolving polycyclic aromatic hydrocarbons in Herbig Ae disks with VISIR-NEAR at the VLT

We use the long-slit spectroscopy mode of the VISIR-NEAR experiment to perform diffraction-limited observations of eight nearby Herbig Ae protoplanetary disks. We extract spectra for various locations along the slit with a spectral resolution of R = 300 and perform a compositional fit at each spatial location using spectral templates of silicates and the four PAH bands. This yields the intensity vs. location profiles of each species. Results. We could obtain spatially-resolved intensity profiles of the PAH emission features in the N-band for five objects (AB Aurigae, HD 97048, HD 100546, HD 163296, and HD 169142). We observe two kinds of PAH emission geometry in our sample: centrally-peaked (HD 97048) and ring-like (AB Aurigae, HD 100546, HD 163296, and potentially HD 169142). Comparing the spatial PAH emission profiles with near-infrared scattered light images, we find a strong correlation in the disk sub-structure but a difference in radial intensity decay rate. The PAH emission shows a less steep decline with distance from the star. Finally, we find a correlation between the presence of (sub-) micron-sized silicate grains leading to the depletion of PAH emission within the inner regions of the disks. In this work, we find the following: (1) PAH emission traces the extent of Herbig Ae disks to a considerable radial distance. (2) The correlation between silicate emission within the inner regions of disks and the depletion of PAH emission can result from dust-mixing and PAH coagulation mechanisms and competition over UV photons. (3) For all objects in our sample, PAHs undergo stochastic heating across the entire spatial extent of the disk and are not saturated. (4) The difference in radial intensity decay rates between the PAHs and scattered-light profiles may be attributed to shadowing and dust-settling effects, which affect the scattering grains more than the PAHs

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

Chapter 70 - Antagonists of Growth Hormone—Releasing Hormone (GHRH) in Cancer

This chapter focuses on potent antagonistic analogs of growth hormone-releasing hormone (GH-RH) in cancer. GHRH antagonists inhibit the growth, tumorigenicity, and metastases of a wide range of human experimental malignancies. GH-RH antagonists bind to pituitary receptors for GH-RH and inhibit the release of GH in vitro and in vivo. The presence of GH-RH ligand was demonstrated in various cancers, suggesting that GH-RH could be an autocrine growth factor. GH-RH antagonists inhibit the growth of various human cancer lines xenografted into nude mice, including breast cancers, prostate cancers, small cell lung carcinomas (SCLC) and non-SCLC, malignant gliomas, renal cell carcinomas, pancreatic cancers, colorectal carcinomas, and lymphomas. These effects of GHRH antagonists could be exerted in part indirectly through inhibition of the secretion of pituitary GH and the resulting reduction in the levels of hepatic IGF-I. However, the principal effect of GH-RH antagonists appears to be the direct suppression of action of the autocrine GHRH and the secretion of IGF-I and IGF-II in tumors, as well as expression of the genes encoding them. These direct effects of GHRH antagonists are exerted on GHRH receptors and their splice variants on tumors. Further development of GH-RH antagonists should lead to potential therapeutic agents for various cancers

Antagonistic Analogs of Growth Hormone-releasing Hormone: New Potential Antitumor Agents

Recently, new potent antagonistic analogs of growth hormone-releasing hormone (GH-RH) have been synthesized. These GH-RH antagonists bind to pituitary receptors for GH-RH and inhibit the release of GH in vitro and in vivo. This suggests that they could be clinically useful in conditions such as acromegaly. The main applications of GH-RH antagonists would be in the field of insulin-like growth factor I (IGF-I)- and IGF-II-dependent cancers. GH-RH antagonists inhibit the growth of various human cancer cell lines xenografted into nude mice, including mammary cancers, androgen-independent prostate cancers, small-cell lung carcinomas, non-small-cell lung carcinomas, renal adenocarcinomas, pancreatic cancers, colorectal carcinomas and malignant gliomas. These effects could, in part, be exerted indirectly through inhibition of the secretion of GH and the resulting reduction in levels of hepatic IGF-I. However, the principal action of GH-RH antagonists in vivo appears to be the direct suppression of the autocrine and/or paracrine production and expression of the genes encoding IGF-I ( IGF1) and IGF-II ( IGF2) in tumors. In vitro, antagonists of GH-RH inhibit the proliferation of mammary, prostatic, pancreatic and colorectal cancer cell lines, reducing the expression of IGF2 mRNA in the cells and the secretion of IGF-II. The presence of the GH-RH ligand has been demonstrated in human ovarian, endometrial, mammary and lung cancers, suggesting that GH-RH could be a growth factor. Further development of GH-RH antagonists should lead to potential therapeutic agents for IGF-dependent cancers

Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of U-87MG Human Glioblastoma in Nude Mice

Antagonists of growth hormone-releasing hormone(GH-RH) inhibit the growth of various cancers by mechanisms that involve the suppression of the insulin-like growth factor (IGF) -I and/or IGF-II. In view of the importance of the IGF system in glioma tumorigenesis, the effects of GH-RH antagonists MZ-5-156 and JV-1-36 were investigated in nude mice bearing subcutaneous and orthotopic xenografts of U-87MG human glioblastomas. After 4 weeks of therapy with MZ-5-156 or JV-1-36 at the dose of 20 µmg/day per animal, the final volume of subcutaneous U-87MG tumors was significantly (P < .01) decreased by 84% and 76%, respectively, as compared with controls. Treatment with GHRH antagonists also reduced tumor weight and the levels of mRNA for IGF receptor type I (IGFR-I). A reduction in the mRNA levels for IGF-II was found in tumors of mice treated with MZ-5-156. Treatment with MZ-5-156 or JV-1-36 also extended the survival of nude mice implanted orthotopically with U-87MG glioblastomas by 81% (P < .005) and 18%, respectively, as compared with the controls. Exposure in vitro to GH-RH antagonists MZ-5-156 or JV-1-36 at 1 MM concentration for 24 hours decreased the tumorigenicity of U-87MG cells in nude mice by 10% to 30% and extended the latency period for the development of subcutaneous palpable tumors by 31% to 56%, as compared with the controls. Exposure of U-87MG cells to GH-RH antagonists in vitro also resulted in a time-dependent increase in the mRNA levels of IGFR-II or a decrease in the mRNA levels of IGFR-I. mRNA for GH-RH was detected in U87MG cells and xenografts implying that GH-RH may play a role in the pathogenesis of this tumor. Our results suggest that GH-RH antagonists MZ-5-156 and JV-136 inhibit the growth of U-87MG human glioblastoma by mechanisms that involve the suppression of IGF system. Antagonistic analogs of GH-RH merit further development for the treatment of malignant glioblastoma

Suppression of tumor growth by growth hormone-releasing hormone antagonist JV-1-36 does not involve the inhibition of autocrine production of insulin-like growth factor II in H-69 small cell lung carcinoma

Although a high antitumor activity of growth hormone releasing hormone (GHRH) antagonists has been demonstrated in various tumors, the mechanism of action of these peptide analogs remains poorly understood. An association has been observed between the antitumor effects of GHRH antagonists and the inhibition of insulin-like growth factors (IGFs), but it is not clear whether the suppression of IGFs is obligatory for the action of GHRH antagonists. In the present study we investigated various components of the IGF system in H-69 small cell lung carcinoma (SCLC) xenografted into nude mice and treated with GHRH antagonist JV-1-36. After 31 days of treatment with JV-1-36, tumor weight was inhibited by about 70% as compared with the controls. Reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated that H-69 tumors express mRNAs for IGF-II and IGF-receptors- (IGFR-) I and II, but not for IGF-I. The levels of mRNA for IGF-II and IGFR-I and -II were not affected by the treatment with JV-1-36. Exposure to antibody IRa, which blocks the binding of IGF-I and -II to IGFR-I, inhibited the proliferation of H-69 cells in vitro, indicating that IGF-II present in the tumors might stimulate the proliferation of H-69 SCLC in an autocrine manner. Collectively our results suggest that inhibition of tumor growth by GHRH antagonists is not associated with the suppression of the autocrine stimulation by IGF-II in H-69 SCLC

GHRH antagonists reduce the invasive and metastatic potential of human cancer cell lines \u3ci\u3ein vitro\u3c/i\u3e

We investigated the effect of a GHRH antagonist, MIA-602 on the metastatic cascade in vitro of three human cancers, DBTRG-05 glioblastoma, MDA-MB-468 estrogen-independent breast, and ES-2 clear cell ovarian cancer. GHRH receptors and their main splice variant, SV1 were detected on all three cell lines. After treatment with MIA-602, the cell viability decreased significantly, significant inhibition of cell invasion was observed and the release of MMPs was significantly decreased. The attachment of cancer cells to fibronectin and matrigel was severely hindered. Wound-healing experiments demonstrated a reduced cellular motility in all three cell lines. The up regulation of caveolin-1 and E-cadherin, and the powerful down regulation of NF-ĸB and β-catenin was detected. Our study suggests that the clinical application of highly potent GHRH antagonists in cancer therapy would be desirable since they inhibit proliferation and metastasis development as well