beta-endorphin and Prostatic-Neoplasms

Two or three decades ago, cancer pain was treated by surgical/chemical hypophysectomy. In one report, the control of central pain (thalamic pain syndrome) was also approached with chemical hypophysectomy. Although in most of the patients these treatments resulted in a decrease in severe pain, concomitantly severe adverse effects (panhypopituitarism, diabetes insipidus and visual dysfunction) occurred in most patients. This historical evidence prompted us to perform Gamma Knife surgery (GKS) for this kind of intractable severe pain using a high irradiation dose to the pituitary stalk/gland. In the majority of patients, marked pain relief was achieved, surprisingly without any of the complications mentioned above.. A prospective multicenter study was conducted to evaluate the efficacy and safety in patients treated in Prague, Hong Kong and Tokyo. Indications of this treatment were: (1) failure of other effective treatment approaches prior to GKS, (2) good general patient condition (Karnofsky performance status >40%), (3) response to morphine for pain control (cancer pain), and (4) no previous radiotherapy of brain metastases (GKS/conventional radiotherapy). Eight patients with severe cancer pain due to bone metastasis and 12 patients with post-stroke thalamic pain syndrome were treated with GKS. The target was the border between the pituitary stalk and gland. Maximum dose was 160 Gy for cancer pain and 140 Gy for central pain. Follow-up included 6 patients (>1 month) with cancer pain and 8 patients (> 6 months) with thalamic pain syndrome.. All patients (6/6) with cancer pain experienced significant pain reduction, and 87.5% (7/8) of the patients with thalamic pain had initially significant pain reduction. In some patients, pain reduction was delayed for several hours. Pain relief was noted within 7 days (median 2 days). No recurrence was observed in the patients with cancer pain. However, in 71.4% (5/7) of the patients with thalamic pain syndrome, disease recurred during the 6-month follow-up. Up to now, other complications have not been observed.. Our clinical study protocol is only preliminary. Further clinical results on the management of thalamic pain are required to develop this treatment protocol. However, efficacy and safety have been shown in all our cases. In our opinion, this treatment has a potential to control severe pain, and GKS will play an important role in the management of intractable pain.

Topics: beta-Endorphin; Bone Neoplasms; Breast Neoplasms; Female; Humans; Hypophysectomy; Male; Pain; Pituitary Gland; Prospective Studies; Prostatic Neoplasms; Radiosurgery; Thalamus; Treatment Outcome

Pituitary adenylate cyclase-activating peptide (PACAP), a cAMP-activating agent, is highly expressed in the hypothalamus during the period when many neuroendocrine cells become differentiated from the neural stem cells (NSCs). Activation of the cAMP system in rat hypothalamic NSCs differentiated these cells into beta-endorphin (BEP)-producing neurons in culture. When these in vitro differentiated neurons were transplanted into the paraventricular nucleus (PVN) of the hypothalamus of an adult rat, they integrated well with the surrounding cells and produced BEP and its precursor gene product, proopiomelanocortin (POMC). Animals with BEP cell transplants demonstrated remarkable protection against carcinogen induction of prostate cancer. Unlike carcinogen-treated animals with control cell transplants, rats with BEP cell transplants showed rare development of glandular hyperplasia, prostatic intraepithelial neoplasia (PIN), or well differentiated adenocarcinoma with invasion after N-methyl-N-nitrosourea (MNU) and testosterone treatments. Rats with the BEP neuron transplants showed increased natural killer (NK) cell cytolytic function in the spleens and peripheral blood mononuclear cells (PBMCs), elevated levels of antiinflammatory cytokine IFN-gamma, and decreased levels of inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in plasma. These results identified a critical role for cAMP in the differentiation of BEP neurons and revealed a previously undescribed role of these neurons in combating the growth and progression of neoplastic conditions like prostate cancer, possibly by increasing the innate immune function and reducing the inflammatory milieu.

Topics: Animals; beta-Endorphin; Cell Death; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cyclic AMP; Female; Hypothalamus; Interferon-gamma; Killer Cells, Natural; Male; Methylnitrosourea; Neurons; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Stem Cells; Testosterone; Tumor Necrosis Factor-alpha

The xenograft line, UCRU-PR-2, has been characterized further. Established from a primary human undifferentiated small cell carcinoma of the prostate, it has been maintained as a stable xenograft line in nude mice and is currently in passage 9. The tumor has maintained the features of small cell undifferentiated carcinoma but shows epithelial as well as neuroendocrine characteristics. In this paper, we describe synthesis and secretion of peptide hormones, ACTH, beta-endorphin and somatostatin in vivo and ACTH and beta-endorphin in vitro by the tumor, UCRU-PR-2. This suggests that the gene for proopiomelanocortin is expressed and that processing of the molecule occurs. This line may yield insights into the histogenesis of the subtypes of prostate cancer, and also aid studies of regulation of ectopic hormone production.

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Carcinoma, Small Cell; Cell Line; Hormones; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Peptide Biosynthesis; Peptides; Prostatic Neoplasms; Transplantation, Heterologous

The effect of opiate receptor agonists upon cell growth of the prostatic carcinoma cell line DU145 were studied. Dynorphin-A increased growth significantly with a peak response at 10(-13) M, of 21 +/- 4% (mean +/- SEM). The dose response curve had a typical inverted-U shape. Dynorphin fragments 1-13 and 1-7 also increased growth at 10(-13) M, while the 2-13 fragment failed to increase growth. Naloxone increased growth at high concentration (10(-7) M) suggesting a stimulatory effect, while at the same time blocking the effect of dynorphin-A. This data demonstrates that agents which stimulate opiate receptors, especially the kappa receptor agonist dynorphin, increase the growth of prostatic carcinoma, and that this effect is controlled by changes at the N-terminal end of the peptide. This effect is blocked by Naloxone.

Topics: beta-Endorphin; Cell Division; Dose-Response Relationship, Drug; Dynorphins; Enkephalin, Leucine; Male; Morphine; Naloxone; Narcotics; Prostatic Neoplasms; Receptors, Opioid; Tumor Cells, Cultured