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Biomedical subjects

T W Redding

Publications and source records attributed to T W Redding.

At least 55 records · Page 3Linked to original sources
PubMed1984

Antitumor effects of analogs of hypothalamic hormones in endocrine-dependent cancers.

A new approach to the treatment of endocrine-dependent tumors based on analogs of hypothalamic hormones is in the early stages of development, but appears promising and significant. Administration of hypothalamic hormones can mimic hypophysectomy and gonadectomy, and is essentially devoid of side effects. A successful use of agonistic analogs of LH-RH for treatment of endocrine-dependent prostate cancer has been documented in several hundred patients. Experimental studies suggest that agonists and/or antagonists of LH-RH might be useful for treatment of breast cancer and pituitary tumors. Our work in animal models also indicates that analogs of somatostatin, alone or combined with LH-RH agonists, could be considered for therapy of chondrosarcomas, osteosarcomas, and pancreatic cancer. Experiments are in progress on the use of LH-RH analogs for treatment of ovarian cancer, neoplasms of the female genital tract, and for protection against gonadal damage during chemotherapy. These investigations should extend the concepts of endocrine treatment of cancers.

Animals↗
PubMed1984

Potential use of analogs of luteinizing hormone-releasing hormones in the treatment of hormone-sensitive neoplasms.

New approaches to the therapy for some endocrine-dependent tumors with analogs of hypothalamic hormones are being developed on the basis of experimental studies in animal models. Analogs of luteinizing hormone-releasing hormones (LH-RH) may open new vistas for the treatment of some hormone-dependent carcinomas. It has been clearly demonstrated that both agonistic and antagonistic analogs of LH-RH can inhibit the growth of rat prostate tumors. A successful treatment of androgen-dependent prostate cancer with agonistic analogs of D-Trp6-LH-RH, D-Ser(But)6des-Gly-NH2(10)-LH-RH ethylamide, and D-Leu6-des-Gly-NH2(10)-LH-RH ethylamide has been documented in several hundred patients. The data accumulated so far from clinical trials suggest that LH-RH agonists can be used as an effective endocrine therapy for prostate carcinoma, therapy avoiding the side effects of estrogen and the psychologic impact of castration. Experimental animal studies and some clinical trials suggest that LH-RH agonists and/or antagonists might also be useful in the treatment of breast cancer. The results of experiments with various hypothalamic analogs in animal models of chondrosarcomas, osteosarcomas, and other tumors appear to be encouraging, but the potential clinical efficacy of LH-RH analogs in the treatment of human hormone-sensitive cancers other than breast and prostate remains to be investigated. The approach to treatment of hormone-dependent tumors based on analogs of hypothalamic hormones might become a useful addition to conventional methods for cancer therapy.

Animals↗
PubMed1983

The presence of LHRH-like receptors in Dunning R3327H prostate tumors.

Quantitative analyses of LH-RH-like membrane receptors were performed in five tumors from the transplantable Dunning R3372H rat prostatic adenocarcinoma. The binding of D-Trp6-LH-RH, an agonist of LH-RH, was observed in all 5 tumors. The antagonist [Ac-Dp-Cl-Phe1,2,D-Trp3,D-Lys6, D-Ala10]-LH-RH was bound to 4 tumors. The apparent equilibrium dissociation constant (Kd) for D-Trp6-LH-RH receptor was from 2.6-3.9 x 10(-10) M. The apparent equilibrium Bmax values (maximum number of binding sites) were from 17.2-86.0 fmol/mg membrane protein for D-Trp6-LH-RH receptor. The Kd for the antagonist was from 2.4-2.7 x 10(-10) M and the Bmax values were from 35.5-66.0 fmol/mg membrane protein. Similar binding studies performed in 6 normal rat prostates showed no binding capacities.

Animals↗
PubMed1983

Inhibition of prostate tumors by agonistic and antagonistic analogs of LH-RH.

We have compared the effects of chronic administration of D-Trp6-LH-RH, a superactive agonist of LH-RH, and a potent antagonist, (NAc-p-Cl-D-Phe1,2,D-Trp3,D-Arg6,D-Ala10)LH-RH, on male Copenhagen F-1 rats bearing the Dunning R-3327H prostate adenocarcinoma. Treatment with 25 micrograms of D-Trp6-LH-RH bid for 21 days decreased the weights of the ventral prostate, testes, and adrenals, but had no effect on the weight of the anterior pituitary gland. Administration of similar doses of the antagonist reduced the weight of the ventral prostate, anterior pituitary gland, and adrenals, but did not change the weight of the testes. Both the agonist and antagonist greatly and significantly reduced tumor weight and volume as compared to controls. Serum LH, prolactin, and testosterone levels in Copenhagen F-1 rats bearing Dunning tumors were significantly decreased after treatment with D-Trp6-LH-RH as well as the antagonist. The inhibition of rat prostate tumors achieved with D-Trp6-LH-RH and the antagonistic analog raised the possibility that these compounds could be used clinically in the treatment of prostate carcinoma and other endocrine-dependent neoplasias. The antagonistic analogs have not yet been tried clinically on a chronic basis. However, the data accumulated so far from clinical trials in men with prostate carcinoma suggest that D-Trp6-LH-RH and other LH-RH agonists can be used for an effective therapy which avoids the side effects of estrogen and the pyschological impact of castration.

Animals↗
PubMed1983

Inhibition of growth of a prolactin-secreting pituitary tumor in rats by analogs of luteinizing hormone-releasing hormone and somatostatin.

We investigated the effects of [D-Trp6]LH-RH [agonistic analog of luteinizing hormone-releasing hormone (LH-RH)], N-Ac-[D-p-Cl-Phe1,2,D-Trp3,D-Phe6,D-Ala10]LH-RH (antagonistic analog), and [D-5-methoxy-Trp8]somatostatin (somatostatin analog) on the growth of the prolactin and corticotropin-secreting pituitary tumor 7315a in female Buffalo rats. Chronic administration of [D-Trp6]LH-RH in a dose of 25 micrograms/day, starting 18 days after inoculation with the tumor, inhibited the growth of the pituitary tumor. Tumor weight and volume also were reduced when this agonist was administered 3 days after inoculation. The antagonistic LH-RH analog, injected in a dose of 50-100 micrograms for 14-24 days, also significantly inhibited the growth of pituitary tumor. Chronic administration of the somatostatin analog in a dose of 25 micrograms twice a day likewise decreased tumor weights in comparison with controls. The inhibition of pituitary tumor growth by LH-RH agonist, LH-RH antagonist, and somatostatin analog was accompanied by a decrease in serum prolactin levels. It was concluded that LH-RH agonist, LH-RH antagonist, and somatostatin analog can inhibit the growth of estrogen-dependent prolactin/corticotropin-secreting pituitary tumor in rats.

Animals↗
PubMed1983

Inhibition of growth of the transplantable rat chondrosarcoma by analogs of hypothalamic hormones.

The Swarm chondrosarcoma is a hormone-responsive tumor whose growth is dependent on growth hormone, somatomedins, and glucocorticoids. Our previous work showed that partial functional hypophysectomy can be achieved by chronic administration of the luteinizing hormone-releasing hormone (LH-RH) analog [D-Trp(6)]LH-RH, which lowers blood levels of LH and follicle-stimulating hormone. We have also demonstrated that somatostatin (SS)-28 or analogs of SS-14 depress serum prolactin, growth hormone, and corticotropin (ACTH) levels. Consequently, we investigated the effect of subcutaneous injection of these analogs on the growth of Swarm chondrosarcoma 3 days after transplanting it into male Sprague-Dawley rats. At autopsy, tumor volume was measured and tumors and various organs were weighed. In rats treated with three different analogs of SS-14, [p-NH(2)-Phe(4)]SS, [D-5-F-Trp(8)]SS, and [D-5-MeO-Trp(8)]SS, in doses of 30 mug once or twice daily for 14-30 days, there was a significant reduction in tumor volume and/or weight as compared with control rats. The longer acting SS-28 or its analog Val-Gly-Tyr-Val-Ile-Leu-Gly-SS-28, given in doses of 30 mug/day for 22-30 days, also significantly decreased tumor weight and/or volume. In three experiments, [D-Trp(6)]LH-RH (30-60 mug/day), administered alone or together with analogs of SS-14, decreased tumor weight and/or volume. Serum growth hormone and prolactin levels in rats bearing the tumors were significantly decreased after treatment with [D-5-F-Trp(8)]SS or with [D-Trp(6)]LH-RH. The inhibition of growth of the Swarm chondrosarcoma in rats by these analogs suggests that they might lead to a new endocrine therapy for chondrosarcomas, osteosarcomas, and related hormone-dependent neoplasias.

Animals↗
PubMed1983

Inhibition of mammary tumor growth in rats and mice by administration of agonistic and antagonistic analogs of luteinizing hormone-releasing hormone.

Experiments were undertaken with estrogen-dependent mammary carcinomas in rats and mice to determine the antitumor activities of agonistic and antagonistic analogs of luteinizing hormone-releasing hormone (LH-RH). Chronic administration of the agonist [D-Trp6]LH-RH or of antagonist 1 ( [NAc-D-p-Cl-Phe1,2-Phe3,D-Arg6-D-Ala10]LH-RH) at doses of 25 and 50 micrograms/day, respectively, for 21 days to mice bearing the MXT mammary carcinoma significantly decreased tumor weight and volume. The weight of the ovaries and serum progesterone levels in mice treated with [D-Trp6]LH-RH or antagonist 1 were also significantly reduced. In rats bearing the MT/W9A mammary adenocarcinoma, chronic administration of [D-Trp6]LH-RH at a dose of 25 micrograms twice a day or of antagonist 2 ( [NAc-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]LH-RH) at a dose of 50 micrograms twice a day for 28 days significantly decreased tumor weight and volume. Chronic treatment with either [D-Trp6]LH-RH or antagonist 2 markedly diminished the weight of the ovaries and serum levels of both estrogen and progesterone. Serum luteinizing hormone was significantly decreased in rats treated with antagonist 2 but not in rats treated with [D-Trp6]LH-RH. There was a significant drop in serum prolactin levels in rats treated with [D-Trp6]LH-RH but not in those receiving antagonist 2. Regression of mammary tumors in rats and mice in response to chronic administration of [D-Trp6]LH-RH and the two antagonistic analogs of LH-RH suggests that these compounds should be considered for the development of a new hormone therapy for breast cancer in women.

Adenocarcinoma↗
PubMed1982

Synthesis and biological properties of ovine corticotropin-releasing factor (CRF).

The 41-residue sequence of recently identified ovine corticotropin-releasing factor (CRF) was assembled on a benzhydrylamine resin support. Deprotection and cleavage from the resin were accomplished by HF treatment. The crude peptide was purified by gel filtration and reverse-phase, medium pressure, followed by high-performance liquid chromatography (HPLC). In addition to the usual criteria, the homogeneity of the final material, obtained in 7% yield, was assessed by the isolation and examination of cyanogen bromide cleavage and tryptic digestion fragments by HPLC and amino acid analysis. The synthetic 41 amino acid CRF stimulated the release of corticotropin (ACTH) in three in vitro systems: isolated rat pituitary quarters, monolayer cultures of dispersed pituitary cells, and superfused pituitary cells on a column, the responses being related to the log-dose of CRF in the range of 0.05-125 ng/ml. The synthetic peptide also augmented in vivo release of ACTH in rats pretreated with chlorpromazine, morphine, and Nembutal, as assessed by the measurement of serum corticosterone. The data indicates chemical purity and high biological activity of synthetic material.

Adrenocorticotropic Hormone↗
PubMed1982

Inhibition of cell growth by a hypothalamic peptide.

A fraction purified from acetic acid extracts of porcine hypothalami was found to contain significant antimitogenic activity when tested in normal and neoplastic cell lines. Addition of this hypothalamic material (1-100 micrograms/ml) to culture media significantly inhibited [3H]thymidine incorporation into cellular DNA in several cell lines. Amino acid incorporation into pituitary proteins and uridine incorporation into RNA were also significantly reduced by this factor(s). Addition to the culture media of this hypothalamic material at 5 micrograms/ml and 50 micrograms/ml per day decreased by 17% and 36%, respectively, cell numbers of 3T6 fibroblast cell cultures. Time-response curves showed that the inhibition of [3H]thymidine incorporation into DNA in 3T6 fibroblast cells begins within 2 hr after adding this fraction to the culture medium. The inhibitory action cannot be explained by a direct cytotoxic effect since 3T6 cells labeled with 51Cr and incubated for 6 hr in the presence of this hypothalamic fraction fail to show an increase in the release of 51Cr into the medium as compared with controls. Incubation with trypsin and chymotrypsin completely abolished the antimitogenic activity of this material and pepsin decreased it. This strongly suggests that the antimitogenic activity exhibited by this fraction is due to a polypeptide(s). These observations provide evidence for the presence in the mammalian hypothalamus of an antimitogenic peptide(s) that may be involved in the regulation of cell proliferation.

Animals↗
PubMed1982

Prostate carcinoma tumor size in rats decreases after administration of antagonists of luteinizing hormone-releasing hormone.

The effects of two potent antagonistic analogues of luteinizing hormone-releasing hormone (LH-RH) on the growth of two different models of rat prostate tumors have been investigated. Chronic administration of [NAc-p-F-DPhe1,p-Cl-DPhe2,DTrp3.6,D-Ala10]LH-RH (antagonist I) at 50 micrograms/day for 21 days significantly inhibited the growth of the chemically induced squamous cell carcinoma 11095 in Fisher 344 male rats. The weights of the pituitary, ventral prostate, and testes were not significantly altered. After 21 days of treatment with this analogue serum luteinizing hormone (lutropin), follicle-stimulating hormone, and testosterone levels were markedly decreased. When male Copenhagen F-1 rats bearing the Dunning 3327H prostate adenocarcinoma were injected with antagonist I at 50 micrograms/day for 6 weeks or with [NAc-p-Cl-DPhe1,2,DTrp3,DPhe6,DAla10]LH-RH (antagonist II) at 50 micrograms/day for 17 days, the percentage increase in tumor volume was decreased to half or less and the actual tumor volume was diminished 34-96% compared to controls. Tumor weight was decreased 30% and 89% after antagonist I and, respectively, compared to untreated controls. The tumor doubling time was 3- to 4-fold longer in rats receiving the inhibitory analogues than in the controls. Treatment with antagonist II decreased the weight of the whole prostate, but neither antagonist changed the weight of testes, anterior pituitary gland, or adrenals. Serum luteinizing hormone, follicle-stimulating hormone, and testosterone levels in Copenhagen F-1 rats bearing Dunning tumors were significantly decreased after treatment with the inhibitory analogues, but progesterone levels were increased. The inhibitory effects of these antagonistic analogues on rat prostate tumors suggest that these compound might be considered in the development of new types of therapy for prostate carcinoma and other endocrine-dependent neoplasias.

Animals↗
PubMed1981

Isolation, structure and synthesis of a heptapeptide with in vitro ACTH-releasing activity from porcine hypothalamus.

Significant CRF activity was found in a fraction with Rf = 0.82-0.7 or VE/VT = 0.41-0.48 obtained by gel filtration of acid extracts of pig hypothalami on Sephadex G-25. The activity of this fraction decreased markedly during subsequent purification, particularly in the last two steps. From this fraction, a heptapeptide with significant ACTH releasing activity in vitro, was isolated in pure state, and its amino acid sequence was established as H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH. This heptapeptide was synthesized by solid phase methods. The CRF activity of synthetic heptapeptide in vitro was low but could be potentiated by a cofactor fraction from rat hypothalamic extract.

Adrenocorticotropic Hormone↗
PubMed1981

Inhibition of prostate tumor growth in two rat models by chronic administration of D-Trp6 analogue of luteinizing hormone-releasing hormone.

We have investigated the effect of the D-Trp6 analogue of luteinizing hormone-releasing hormone (LH-RH), a superactive analogue of LH-RH, on the growth of two different models of prostate tumors in rats. Chronic administration of D-Trp6-LH-RH in a dose of 25 micrograms/day for 14-21 days significantly inhibited the growth of the chemically induced squamous cell carcinoma 11095 in Fisher 344 male rats. The weights of the ventral prostate and testes were also significantly reduced by treatment with this analogue. After 21 days of treatment, the animals no longer showed increases in serum luteinizing hormone and follicle-stimulating hormone levels in response to D-Trp6-LH-RH. Treatment of male Copenhagen F-1 rats bearing the Dunning 3327 prostate adenocarcinoma with 25 micrograms of D-Trp6-LH-RH per day for 42 days decreased the weights of both the ventral prostate and testes but had no effect on the weight of the anterior pituitary gland. The percentage increase in tumor volume was decreased to one-third and the actual tumor weight was decreased by 58% compared to untreated controls. The tumor doubling time was more than 4 times longer in rats receiving D-Trp6-LH-RH than in controls. Serum levels of luteinizing hormone and follicle-stimulating hormone were significantly decreased in rats receiving this analogue. In both Fisher 344 and Copenhagen F-1 rats, serum prolactin and testosterone levels were significantly decreased after treatment with D-Trp6-LH-RH, whereas progesterone levels were increased.

Animals↗
PubMed1981

High molecular weight peptide with corticotropin-releasing factor activity from porcine hypothalami.

The presence of a corticotropin-releasing factor (CRF) behaving as a peptide with a molecular weight of about 5000 was established after purification of porcine hypothalamic extracts by gel filtration on Sephadex G-25 and then on Sephadex G-50. Purified CRF stimulated the release of corticotropin (ACTH) in three in vitro systems: isolated rat pituitary quarters, monolayer cultures of dispersed pituitary cells, and superfused pituitary cells on a column. A linear logarithmic dose-response relationship existed between 50 and 200 micrograms of CRF preparations per ml and the total amount of ACTH released by the superfused pituitary cells. The pituitary ACTH response to CRF in the pituitary quarters system was also approximately linearly related to the logarithm of the dose of CRF. CRF also stimulated in vivo release of ACTH in rats pretreated with chlorpromazine, morphine, and Nembutal. CRF activity was labile to digestion with trypsin and chymotrypsin and was partially destroyed by pepsin. The evidence indicates that CRF of porcine origin is a polypeptide of a higher molecular weight than previously assumed.

Animals↗
PubMed1980

Isolation and structure of several peptides from porcine hypothalami.

Ten peptides were isolated from porcine hypothalami and structurally elucidated. These included four dipeptides Arg-Phe, Phe-Tyr, Val-Trp, and Tyr-Phe; a tripeptide Lys-Phe-Tyr; two tetrapeptides Gly-Lys-Val-Asn and Phe-Glu-His-Glu, a nonapeptide Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe; a decapeptide Leu-Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe and a hexadecapeptide Phe-Leu-Gly-Phe-Pro-Thr-Thr-Lys-Thr-Tyr-Phe-Pro-His-Phe-Asn-Leu. The tetrapeptide Gly-Lys-Val-Asn, the nonapeptide, the decapeptide and the hexadecapeptide most probably represent artifact fragments of alpha- and beta-chains of porcine hemoglobin. The natural or synthetic Gly-Lys-Val-Asn and Phe-Glu-His-Glu had some growth hormone releasing activity while Val-Trp, Tyr-Phe and Lys-Phe-Tyr had slight prolactin releasing activity. The biological activities of other peptides have not been determined yet.

Amino Acid Sequence↗
PubMed1980

[Phe4]somatostatin: a potent, selective inhibitor of growth hormone release.

[Phe4]Somatostatin was twice as active as somatostatin (SS) in suppressing rat growth hormone release in vitro but had only weak activity toward inhibition of insulin and glucagon release in vivo. The ability of this analogue to inhibit growth hormone release more actively than SS was confirmed in vivo by two separately designed bioassays. Further structure/activity studies of position 4 were carried out with [Glu4]SS, [Thr4]SS, and des-Lys4-SS, all of which had negligible inhibiting activity in the pituitary and pancreas. In this context the strikingly selective activity of [Phe4]SS suggests a fundamental difference in the SS receptors of pituitary and pancreas and the normal side-chain basicity of position 4 appears to be more important for action in pancreas than in pituitary. [Phe4]SS has properties that may be useful in the development of agents for the treatment of acromegaly or other disorders associated with increased growth hormone levels.

Amino Acid Sequence↗
PubMed1980

Synthesis and biological actions of prosomatostatin.

The recently isolated 28-residue sequence of prosomatostatin, a putative somatostatin precursor from pig hypothalamus and intestine, was synthesized by solid-phase methodology, characterized, and tested in rats for its effects on the release of insulin, glucagon, growth hormone, and prolactin. The synthetic product strongly suppressed plasma levels of insulin, glucagon, and growth hormone, and it appeared to be more active in the pancreas than in the pituitary. It inhibited insulin release about 5 times more effectively than somatostatin on a weight basis. The prohormone also suppressed growth hormone and prolactin levels in vitro. A time-course experiment for the effect of prosomatostatin on growth hormone release in vivo showed a significant suppression of plasma growth hormone for at least 90 min.

Animals↗
PubMed1980

Isolation, structure, biological characterization, and synthesis of beta-[Tyr9]melanotropin-(9-18) decapeptide from pig hypothalami.

A decapeptide with the amino acid sequence H-Tyr-Phe-Arg-Trp-Gly-Ser-Pro-Pro-Lys-Asp-OH was isolated from acid extracts of porcine hypothalami, structurally and biologically characterized, and synthesized. Except for the NH2-terminal tyrosine, this decapeptide corresponds to the amino acid sequences 9-18 of porcine beta-melanotropin (beta-MSH) and 49-58 of porcine beta-lipotropin (beta-LPH); it also has a tetrapeptide sequence of amino acids (Phe-Arg-Trp-Gly) common to the 7-10 sequences in corticotropin (ACTH) and alpha-MSH. beta-MSH, beta-LPH, alphaMSH, and ACTH from various species all have a histidine residue in the position immediately preceding the common sequence, and the occurrence of a natural peptide with the tyrosine residue in the corresponding site has not been previously reported. This suggests that the beta-[Tyr9]MSH-(9-18) decapeptide might be a fragment of a still larger precursor (prohormone) possibly related to beta-LPH.

Adrenocorticotropic Hormone↗