Histologic changes in the rat prostate cancer model after treatment with somatostatin analogs and D‐Trp‐6‐LH‐RH

Zalatnai, Attila; Paz-Bouza, J.I.; Redding, Tommie W.

doi:10.1002/pros.2990120111

Cited by 26 publications

(12 citation statements)

References 20 publications

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“…Dunning R-3327H rats (with androgensensitive PC) were treated with modern SST analogs (Sandostatin, RC-160, RC-121) alone or combined with D-Trp6-LHRH analog or castration [71][72][73][74]. Final tumor volume, percentage change from initial tumor and final tumor weight were decreased due to the inhibitory effect of LHRH analog (or castration), effects which were potentiated by the superactive SST analogs, i.e.…”

Section: In Vitro and In Vivo Studies Of The Antitumor Actions Of Sstmentioning

confidence: 99%

Octreotide in the Management of Hormone-Refractory Prostate Cancer

Vainas

2001

Chemotherapy

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Patients with advanced or metastatic prostate cancer (PC), a partially hormone-resistant disease, will require some form of hormonal manipulations or some new therapeutic modalities. Octreotide, as somatostatin (SST) analogs, has been found to inhibit the growth of experimental PCs via several mechanisms, as indirect antihormonal and direct antimitogenic actions, mainly due to inhibition of SST receptor subtypes (SSTR-1–5). Sporadic clinical trials with octreotide (alone or with a complete antiandrogen blockade) treatment of patients with advanced stage D2 PC demonstrated promising results. Unfortunately, at present these clinical trials have some disadvantages and leave some uncertainty with regard to the trial design, the SSTR subtype determination and tumor localization with SSTR scintigraphy before the start of a selective SST analog, and finally the randomization in groups according to hormone resistance, dosage regimen and route of administration.

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Section: In Vitro and In Vivo Studies Of The Antitumor Actions Of Sstmentioning

confidence: 99%

Octreotide in the Management of Hormone-Refractory Prostate Cancer

Vainas

2001

Chemotherapy

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“…Perhaps the greatest potential for the application of somatostatin analogs is in the treatment of cancer (4,5). Analogs of somatostatin have been shown to be effective against pancreatic (6), breast (7), bone (8,9), and prostate (10,11) cancers. Various brain tumors (meningiomas, astrocytomas, oligodendrogliomas, ganglioneuroblastomas, medulloblastomas) have been shown to have somatostatin receptors (12)(13)(14)(15)(16), raising the possibility that somatostatin analogs could be used in the localization and treatment of these tumors.…”

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confidence: 99%

“…Many analogs show selectivity in their activities. For example, RC-121 is about 100 times more potent than somatostatin- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) tetradecapeptide in the inhibition of growth hormone release but <5 times more potent in the inhibition of gastric acid release (17,18).…”

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confidence: 99%

“…In contrast, essentially no work has been done to investigate the ability of somatostatin analogs to cross the BBB, although it is known that radioactively iodinated Tyrsomatostatin- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) pentadecapeptide can cross (19). This relationship to the BBB has therapeutic potential both for the development of compounds that cross the BBB to possibly treat some brain tumors and for the development of peripherally active compounds that cross poorly so as to exert minimal side effects on CNS function.…”

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confidence: 99%

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Permeability of the murine blood-brain barrier to some octapeptide analogs of somatostatin.

Banks

Barrera

Fasold³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Analogs of somatostatin are being investigated clinically for the treatment of various malignancies, including brain tumors. We studied the ability of three therapeutically promising radioactively labeled somatostatin octapeptide analogs, RC-160, RC-121, and RC-161, to cross the blood-brain barrier (BBB) after peripheral or central injection. After i.v. injection, intact RC-160 was recovered from the blood and the brain. The entry rates were different for each compound but were generally low. By contrast, entry across the intact BBB increased 220 times when RC-160 was given in a serum-free perfusate. This suggests that some serum-related factor, probably the previously described protein binding or an aggregation-promoting factor, is the main determinant in limiting the blood-to-brain passage of somatostatin analogs. Entry into the brain was not inhibited by the addition of unlabeled analog to the perfusate, showing that passage was probably by diffusion across the membranes that comprise the BBB rather than by saturable transport. By contrast, a saturable system was found to transport peptide out of the central nervous system (CNS). The clearance from the CNS of RC-160 and RC-121, but not RC-161, was faster than could be accounted for by reabsorption of cerebrospinal fluid. Transport of radioactively labeled RC-160 out of the CNS was inhibited by unlabeled RC-160 or somatostatin but was not affected by some other peptides known to cross the BBB by their own transport systems. More than 80% of the radioactivity recovered from the blood after intracerebroventricular injection of RC-160 was eluted by HPLC at the position of the labeled analog, showing that the peptide had crossed the BBB in intact form. Our results indicate the presence of a saturable transport system in one direction across the BBB for some superactive analogs of somatostatin. Several problems impede the therapeutic use of naturally occurring peptides, including poor absorption by the gastrointestinal tract, a short half-life in the circulation, and multiple actions. For use in the central nervous system (CNS), limited passage across the blood-brain barrier (BBB) may also be a factor. Most of these problems have been solved in the case of somatostatin by the development of analogs. Circulating half-life has been increased by the development of enzymatically resistant analogs. In addition, the administration of the analogs in sustained-delivery systems (microcapsules) permits the maintenance of high therapeutic blood levels (6, 10, 17). Many analogs show selectivity in their activities. For example, RC-121 is about 100 times more potent than somatostatin-(1-14) tetradecapeptide in the inhibition of growth hormone release but <5 times more potent in the inhibition of gastric acid release (17,18).In contrast, essentially no work has been done to investigate the ability of somatostatin analogs to cross the BBB, although it is known that radioactively iodinated Tyrsomatostatin-(1-14) pentadecapeptide can cross (19). This relationship to the BBB...

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“…(J Clin Endocrinol Metab 82: 2566 -2569, 1997) A ROLE for SRIH in the control of prostate growth or function has been evidenced, even if its mechanism is still under discussion (1)(2)(3)(4). SSTR3 messenger RNA was undetectable in normal and cancer EC, whereas SSTR4 and SSTR5 were present in both cell types.…”

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confidence: 99%

Different Expression Patterns of Somatostatin Receptor Subtypes in Cultured Epithelial Cells from Human Normal Prostate and Prostate Cancer1

Sinisi

Bellastella

Prezioso³

et al. 1997

The Journal of Clinical Endocrinology &Amp; Metabolism

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The transcripts of five SRIH receptor subtypes (SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5) were investigated by RT-PCR in epithelial cells (EC) and stromal cells (SC) from primary cultures of five normal human prostates and six prostate cancers. Primary cultures of prostate EC were established in serum-free keratynocyte medium with 5% FCS, epidermal growth factor, and bovine pituitary extract; SC were cultured in MEM with 10% FCS. Total RNA was extracted from EC and SC using a modified guanidine thiocyanate method. RT-PCR was performed after deoxyribonuclease treatment, using SSTR1-, SSTR2-, SSTR3-, SSTR4-, and SSTR5-specific-primers and adding glyceraldehyde-3-phosphate dehydrogenase-specific primers as internal control. A PCR product of the expected size of 334 bp, corresponding to SSTR1, was expressed only in EC from prostate cancer, whereas the expected 461-bp product of SSTR2 was found only in EC from normal prostate. SSTR3 messenger RNA was undetectable in normal and cancer EC, whereas SSTR4 and SSTR5 were present in both cell types. SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 messenger RNAs were not expressed in SC from both normal and cancer prostates. The RT-PCR method clearly demonstrated SSTRs' expression in the human prostate EC in vitro with differences between normal and tumoral samples. Our results may explain the ineffectiveness of some SSTR2 selective SRIH analogues in the treatment of prostate cancer and suggest that the absence of SSTR2 could represent a growth advantage in prostate cancer.

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Histologic changes in the rat prostate cancer model after treatment with somatostatin analogs and D‐Trp‐6‐LH‐RH

Cited by 26 publications

References 20 publications

Octreotide in the Management of Hormone-Refractory Prostate Cancer

Octreotide in the Management of Hormone-Refractory Prostate Cancer

Permeability of the murine blood-brain barrier to some octapeptide analogs of somatostatin.

Different Expression Patterns of Somatostatin Receptor Subtypes in Cultured Epithelial Cells from Human Normal Prostate and Prostate Cancer1

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