The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma

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Somatostatin Receptors as Molecular Targets in Human Uveal Melanoma

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Effect of drought on yield components of maize hybrids (Zea mays L)

When investigating drought tolerance, it must not be forgotten that drought stress is a complex phenomenon ex¬hibiting quite different characters in different years and locations. For this reason, the plant response to drought is also a complex process. In our study, 83 maize hybrids originating from various countries were investigated over a period of two years, under irrigated and non-irrigated conditions. The drought tolerance of plants in the non-irrigated plots was analysed in terms of flowering synchrony and yield components. It could be concluded from the results that in response to long-term water deficit the period between tasselling and silking became longer, while the analysis of yield components revealed the greatest reductions in the number of kernels per ear and in the proportion of seed set. As the degree of proterandry increased, there was a decline in the grain yield, confirming that the analysis of this trait could be a way of predicting drought tolerance. Considerable differences in drought tolerance were observed between the genetic materials included in the analysis, suggesting the presence among these parental lines and hybrids of genotypes resistant to long-term water deficit, suitable for cultivation under dry conditions. An analysis of correlations between the traits revealed that proterandry should be treated as a priority trait when investigating drought stress tolerance, as better predictions can be made of both drought tolerance and potential yields, leading to more reliable selection for higher yields

Powerful Inhibition of Experimental Human Pancreatic Cancers by Receptor Targeted Cytotoxic LH-RH analog AEZS-108

Pancreatic carcinoma is one of the cancers with the worse prognosis, thus any therapeutic improvement is imperative. Cytotoxic LH-RH analog, AN-152 (proprietary designation, AEZS-108), consisting of doxorubicin (DOX) conjugated to D-Lys6LH-RH, is now in clinical trials for targeted therapy of several sex hormone-dependent tumors that express LH-RH receptors. We investigated LH-RH receptors in human pancreatic carcinoma and the effects of AN-152 (AEZS-108) on experimental pancreatic cancers. We determined LH-RH receptor presence in human pancreatic cancer samples by immunohistochemistry and, in three human pancreatic cancer lines (SW-1990, Panc-1 and CFPAC-1), by binding assays and Western blotting. The effects of the cytotoxic LH-RH analog were investigated on growth of these same cancer lines xenografted into nude mice. We also analyzed differences between the antitumor effects of the cytotoxic analog and its cytotoxic radical alone, doxorubicin (DOX), on the expression of cancer-related genes by PCR arrays. LH-RH receptors were expressed in two randomly selected surgically removed human pancreatic cancer samples and in all three cancer lines. Cytotoxic LH-RH analogs powerfully inhibited growth of all three tumor lines in nude mice; AN-152 was significantly stronger than DOX on Panc-1 and CFPAC-1 cancers. PCR array showed that cytotoxic LH-RH analog AN-152 affected the expression of genes associated with cellular migration, invasion, metastasis and angiogenesis more favorably than DOX, however the changes in gene expression varied considerably among the three cancer lines. Cytotoxic LH-RH analog, AEZS-108, may be a useful agent for the treatment of LH-RH receptor positive advanced pancreatic carcinoma

Expression of Somatostatin Receptor Subtypes (SSTR-1–SSTR-5) in Pediatric Hematological and Oncological Disorders

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Reduction in receptors for bombesin and epidermal growth factor in xenografts of human small-cell lung cancer after treatment with bombesin antagonist RC-3095

Antagonists of bombesin/gastrin-releasing peptide (BN/GRP) have been developed to inhibit the stimulatory effects of BN/GRP on the mitogenesis of tumor cells such as human small-cell lung carcinoma (SCLC). The mode of action of these antagonists is not completely understood. In this study, we evaluated the effect of BN/GRP antagonist RC-3095 on receptors for BN/GRP and epidermal growth factor (EGF) in H-128 human SCLC line xenografted into nude mice. Treatment with RC-3095, administered s.c. at a dose of 20 μg/day per animal for 4 weeks caused a 70% reduction in tumor volume and weight. Membrane receptors for BN/GRP and EGF were characterized in untreated and treated animals. In the control group, [(125)I-Tyr(4)]BN was bound to a single class of specific, high affinity binding sites with a dissociation constant (K(d)) = 6.55 ± 0.93 nM and maximal binding capacity (B(max)) = 512.8 ± 34.8 fmol/mg membrane protein. Therapy with RC-3095 decreased the concentration of BN/GRP receptors on H-128 SCLC tumor membranes. Specific, high affinity binding sites for EGF with K(d) = 1.78 ± 0.26 nM and B(max) = 216.8 ± 19.6 fmol/mg membrane protein were also found on the untreated H-128 SCLC tumors. Treatment with RC-3095 significantly decreased B(max) of receptors for EGF. Our results indicate that the suppression of growth of H-128 SCLC by BN antagonist RC-3095 is accompanied by a decrease in the number of receptors for both BN/GRP and EGF. These observations are in agreement with the results obtained in other experimental cancers. The findings on antagonist RC-3095 reinforce the view that both BN/GRP and EGF receptors participate in a cascade of events involved in the growth of SCLC and other cancers. Although the complete mechanisms of action of antagonist RC-3095 remain to be elucidated, the antitumor effect could be the result of the fall in the EGF receptor number, which might lead to a decrease in EGF receptor autophosphorylation

Targeting to Peptide Receptors

This chapter contains sections titled: Introduction Rationale for the Concept of Delivery to Peptide Receptors Example 1: Cytotoxic Analogs of LHRH1 Example 2: Targeted Cytotoxic Somatostatin Analogs Example 3: Cytotoxic Analogs of Bombesin/Gastrin‐Releasing Peptide Example 4: Antagonists of GHRH Conclusions and Perspectives Acknowledgments Reference

Somatostatin analog RC-160 and bombesin/gastrin-releasing peptide antagonist RC-3095 inhibit the growth of androgen-independent DU-145 human prostate cancer line in nude mice

Nude mice bearing xenografts of the androgen-independent human prostate cancer DU-145 were treated for 4–5 weeks with somatostatin analog RC-160 or the bombesin/gastrin-releasing peptide (GRP) antagonist RC-3095. Tumor growth in animals treated with somatostain analog RC-160 at a dose of 100 μg/day s.c. was significantly inhibited within 14 days of the start of the experiment. At necropsy, in mice given RC-160, tumor weight and volume were significantly decreased compared with control mice. Treatment with RC-3095 at a dose of 20 μg/day s.c. also suppressed tumor growth, the inhibition being significant after 2 weeks, but the reduction in tumor volume and weight was smaller than that produced by RC-160. Therapy with RC-160 significantly decreased serum growth hormone and gastrin levels. Specific binding sites for bombesin, somatostatin and epidermal growth factor (EGF) were found in the DU-145 tumor membranes. Receptors for EGF were significantly down-regulated after therapy with RC-3095 and RC-160. The finding that somatostatin analog RC-160 and bombesin/GRP antagonist RC-3095 inhibit the growth of androgen-independent prostate tumors in mice might be of practical importance for human prostate cancer therapy