A clinical overview of carcinoid tumors: perspectives for improvement in treatment using peptide analogs (review).

Carcinoid tumors were first described more than a century ago, but the treatment of patients with advanced disease remains a challenge to physicians. The etiology of carcinoid tumors, the biologic determinants of the growth of these malignancies, as well as the high frequency of multiple carcinoid and/or non-carcinoid tumors in patients with this disease also remain to be elucidated. A 5-decade analysis of 13,715 carcinoid tumors in the USA showed that distant metastases were demonstrated at the time of diagnosis in 12.9% of patients with this neoplasia. The overall 5-year survival rate for all patients with carcinoids regardless of the site, was reported to be 67.2%. The prognosis of patients with early stage disease is good and surgical resection is the standard form of treatment. The resection of local or regional metastases can result in cure for some cases. However, patients with metastatic dissemination have poor outcomes since chemotherapy is generally ineffective. Surgical resection of isolated hepatic metastases, surgical hepatic artery ligation or embolization produce responses in selected patients. Radiation therapy may ease the pain of bone metastases. The administration of long acting analogs of somatostatin can control the symptoms of diarrhea and flushing in patients with the malignant carcinoid syndrome. However, a complete regression of metastatic carcinoid tumors following the administration of somatostatin analog octreotide has been reported so far in only 3 cases. Other modalities of treatment, including liver transplantation and the administration of radiolabeled somatostatin analogs have likewise been applied in patients with advanced disease. It is expected that advances in proteomics research will contribute to our understanding of the mechanisms of diseases and aid in designing new drugs.

Response of patients with advanced prostatic cancer to administration of somatostatin analog RC-160 (vapreotide) at the time of relapse.

BACKGROUND: The aim of this study was to evaluate the effects of administration of the somatostatin analog RC-160 (vapreotide) at the time of relapse in patients with androgen independent prostate cancer. METHODS: Our study included 13 patients with biopsy-proven prostate cancer, stage D3. Eight patients had been treated with a depot formulation of the agonist D-Trp-6-LH-RH, with a median remission time of 68 (range 48-102 months). Five patients were initially treated by surgical orchiectomy, but relapsed after a median time of 33 months (range 17-91 months). A new remission period with a median duration of 10 months (range 2-29 months) was induced with Ketoconazole in the orchiectomy group. At the relapse time, all the patients received 1 mg of vapreotide t.i.d., by subcutaneous route, in addition to D-Trp-6-LH-RH, or Ketoconazole in the orchiectomy group. RESULTS: Eight of 13 patients demonstrated clinical improvement after 3 months of therapy with vapreotide, six showing a decrease in serum prostate specific antigen (PSA) from 234.5 +/- 308.5 to 68.2 +/- 60.5 ng/ml (mean decline 71 +/- 8%; P < 0.05). Two additional patients presented a fall in serum prostatic acid phosphatase (PAP). Responding patients showed a decrease in the bone pain score from 2.62 +/- 0.48 to 0.37 +/- 0.69 and an increase in the Karnofsky performance status from 72.3 +/- 4.21 to 83.6 +/- 23.2 (P < 0.05). In accord with the ECOG criteria, two patients had a complete response; four had partial response, and two had a stable response. Four patients did not respond and one was not evaluable. Two patients died in remission, one at 16 months due to myocardial infarction and the other at 24 months due to pneumonia. Three patients relapsed at 5, 17, and 19 months respectively. Three patients who have been followed-up for more than 3 years continued in remission (79, 45, and 45 months) respectively. Vapreotide was well tolerated, only three patients having transitory mild diarrhea. CONCLUSIONS: Our results indicate that therapy with the somatostatin analog vapreotide at the time of relapse can induce objective clinical responses in some patients with prostate cancer who are refractory to androgen ablation induced by LH-RH analogs or orchiectomy.

Absence of binding of targeted analogs of somatostatin carrying cytotoxic radicals or radionuclides to growth hormone secretagogue receptors on human myocardium.

Various peripheral human tissues express receptors for growth hormone secretagogue (GHS), the highest density being in the myocardium. It was also reported that some octapeptide analogs of somatostatin (SRIH) can displace radiolabeled Tyr-Ala-hexarelin from GHS receptors on the human pituitary and heart. Thus, it is possible that radionuclide analogs of SRIH such as OctreoScan and recently developed cytotoxic SRIH analogs containing doxorubicin (DOX) intended for targeted tumor therapy, could bind to these GHS receptors, compromising the safety of compounds of this type. Therefore, we determined the binding of OctreoScan and two cytotoxic SRIH analogs consisting of octapeptide carrier RC-121 and DOX (AN-162) or 2-pyrrolino-DOX (AN-238) to human myocardium specimens. None of these compounds displayed specific binding to the human heart indicating that the clinical use of SRIH analogs linked to anthracyclines or radionuclides should not be associated with increased cardiac side effects.

Desaparecimento radiológico de metástases pulmonares num paciente com carcinoma da próstata depois do tratamento com um LH-RH agonista / Radiological regression of lung metastasis in patient with carcinoma of the prostate after the treatment with LH-RH antaganist

Paciente com carcinoma de próstata, retençäo urinária, metástase pulmonar e metástase ósseas foi tratado com D-Trp-6-LH-RH (decapeptyl) por 11 meses. Após 4 meses, houve regressäo das metástases ósseas e pulmonares e alívio da obstruçäo urinária. Apesar desse tratamento ter sido interrompido há mais de 18 meses, o paciente continua assintomático e sem recorrência das metástases ósseas e pulmonares

Acción inhibitoria selectiva del análogo D5-F-TrP8-D-Cys14 somatostatina sobre la liberación de insulina, hormona del crecimiento y glucagon, inducida con arginina en individuos normales / Selective inhibitory effect of the analog D5-F-TrP8-D-Cys14 somatostatin on the arginine induced release of insulin, growth hormone and glucagon, in normal human beings

Se estudió en un grupo de individuos normales la acción de varias dosis de somatostatina y del análogo D5-F-TrP8-D-Cys14-SS sobre la liberación inducida por arginina de insulina, glucagon y hormona de crecimiento (HC). La somatostatina en dosis de 100 g/h suprimió la liberación de insulina, glucagon y HC. El análogo D5-F-TrP8-D-Cys14-SS en dosis de 10 a 20 g/h inhibió a la HC y al glucagon, pero no a la insulina. Estos resultados muestran que es posible obtener análogos de la somatostatina que supriman en forma selectiva a la liberación de insulina, lo que puede ser de gran valor clínico en el manejo de diabetes mellitus, acromegalia, pancreatitis y úlcera péptica

Regulacion peptidergica del apetito. / Peptidergic appetite regulation

La funcion del hipotalamo en la regulacion del apetito se basa en el conocimiento de areas especificas cuya estimulacion o destruccion produce efectos definidos de hiperfagia o de afagia, pero hasta el momento no se ha identificado el mecanismo. Desde hace mas de 15 anos se postulo que la regulacion del apetito podria efectuarse por un mecanismo humoral, mas que neurogeno, y que la substancia causante podria ser elaborada por el hipotalamo. Este enunciado se apoya con la identificacion de varias de las hormonas tipicamente gastrointestinales, que tambien se encuentran en tejido nervioso central, especialmente en hipotalamo, en donde pueden participar en la regulacion del apetito. Recientemente se ha encontrado que tienen tambien efecto en la regulacion del apetito otros peptidos no relacionados con el tubo gastrointestinal.Describimos algunos de los hallazgos mas importantes que apoyan la participacion peptidergica a nivel hipotalamico en el complejo de la regulacion del apetito