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

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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 ,ug/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 ,ug/ml and 50 ,ug/ml per day decreased by 17% and 36%, respectively, cell numbers of 3T6 fibreblast 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 5"Cr and incubated for 6 hr in the presence of this hypothalamic fraction fail to show an increase in the release of 5"Cr 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.Cell growth appears to be regulated not only by accessibility ofnutritional elements but also by a multiplicity ofstimulatory, inhibitory, and synergistic hormones -and growth factors (1-4). Several polypeptides purified from various tissues may regulate cell growth rate, but the mechanisms of this regulation are poorly understood. Fibroblast growth factor, a basic polypeptide isolated from bovine brain and pituitary tissue, is a potent mitogen for mesoderm derived cells, while epidermal growth factor, an acidic polypeptide isolated from mouse submaxillary glands, stimulates the proliferation of ectoderm-derived cells (2, 3). Nerve growth factor, also isolated from mouse submaxillary tissue, is a polypeptide capable of stimulating axonal outgrowth from sympathetic ganglia and of interacting with a variety ofother neural tissues (4, 5). Other peptides that stimulate cell growth have been purified from serum and platelets (6-8).Several tissue-specific and nonspecific cell growth inhibitors extracted from the liver and kidney have been shown to exert their inhibitory properties by depriving the cells of arginine (an arginase activity), degrading thymidine, or inhibiting thymidine phosphorylation (or combinations thereof) (9-12). Beall et aL (13) claimed that peptides found in normal human urine inhibit growth and DNA synthesis more in neoplastic than in normal cells. Recently, Letnansky (14) reported that a peptide isolated from bovine placenta inhibits thymidine incorporation into DNA and tumor growth to a greater exte...

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of cell growth by a hypothalamic peptide.

Redding¹,

Schally²

1982

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“…Inhibition of the growth of endocrine-dependent mammary, prostate, and pituitary tumors by analogs of hypothalamic hormones has recently been demonstrated (22)(23)(24) In the second experiment with hamsters bearing the ductal pancreatic adenocarcinoma ( (5)(6)(7). Although secretin is not as potent as CCK, it also increases pancreatic weight, DNA, RNA, and protein content (7).…”

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confidence: 99%

Inhibition of growth of pancreatic carcinomas in animal models by analogs of hypothalamic hormones.

Redding¹,

Schally²

1984

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141

953Retraction. We now observe alterations in a number of the properties of arl mutants of Escherichia coli; some of these properties were originally described by us in a paper entitled "DNA from recombinogenic bacteriophages generated by arn mutants of Escherichia coli is cleaved by single-strandspecific endonuclease Si", John B. Hays and Brent E. Korba, which appeared in number 12, December 1979, of Proc. Natl. Acad. Sci. USA (76,(6066)(6067)(6068)(6069)(6070). With respect to these latter phenomena, we now find that X phages grown on arl bacteria ("Arl-phages") recombine only 1.2-1.5 rather than 3-5 times as much as "Arl+" phages in subsequent onestep-growth infections, and DNA from Arl-phages no longer appears sensitive to the single-strand-specific S1 nuclease. Some arl phenomena described elsewhere-e.g., decreased resistance to EcoRII restriction by arl phages and enhanced recombination of Arl-plasmids-remain approximately unchanged. The phage-growth properties of both wild-type and arl bacteria using our standard phage growth medium are greatly altered from those described previously, and some genetic properties of the mutants appear changed. It remains to be determined to what extent alterations in arl properties are due to changes in growth medium and/or genetic instability. Fuller accounts of the present status of arl phenomena appear elsewhere (Hays, J. B. & Korba, B. E., J. Mol. Biol. and Cell, in press).Correction. In the article "Inhibition of growth of pancreatic carcinomas in animal models by analogs of hypothalamic hormones" by

“…This highly active agonistic analog of LH-RH has been shown to exert paradoxical inhibitory effects on the pituitary-gonadal axis in both animals and human beings when given chronically (2,3). This inhibition of reproductive functions produced by chronic administration of LH-RH and other LH-RH agonists has been utilized to induce a regression of various hormone-sensitive neoplasms such as mammary carcinomas, prostate tumors, and pituitary tumors (4)(5)(6)(7). It has been shown that long-te~rm administration of agonistic and antagonistic analogs of LH-RH inhibited the growth of the 7315a transplantable rat pituitary tumor, which secretes both prolactin (PRL) and corticotropin (ACTH) (6,7).…”

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confidence: 99%

“…This inhibition of reproductive functions produced by chronic administration of LH-RH and other LH-RH agonists has been utilized to induce a regression of various hormone-sensitive neoplasms such as mammary carcinomas, prostate tumors, and pituitary tumors (4)(5)(6)(7). It has been shown that long-te~rm administration of agonistic and antagonistic analogs of LH-RH inhibited the growth of the 7315a transplantable rat pituitary tumor, which secretes both prolactin (PRL) and corticotropin (ACTH) (6,7). In order to study further the inhibitory effect of [D-Trp6]LH-RH on pituitary tumors, we decided to extend our investigations to the PRL-and growth hormone (GH)-producing GH3 rat pituitary tumor.…”

mentioning

confidence: 99%

Inhibition of growth of a prolactin and growth hormone-secreting pituitary tumor in rats by D-tryptophan-6 analog of luteinizing hormone-releasing hormone.

Torres‐Alemán¹,

Redding²

1985

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The effect of long-term administration of analogs of luteinizing hormone-releasing hormone (LH-RH) and somatostatin on the growth of the growth hormone (GH)-and prolactin (PRL)-secreting rat pituitary GH3 tumor was investigated. Daily administration of tg/day) (Oss, Holland). Somatostatin analog cyclo(Pro-Phe-DTrp-Lys-Thr-Phe) (Veber cyclic hexapeptide) (12) was synthesized in our laboratory or supplied by J. Sandow and R. Geiger (Hoechst, Frankfurt M, FRG). Somatostatin analog D-Phe-Cys-Phe-t-Trp-Lys-Thr-Cys-Thr-NH2 related to the octapeptide of Bauer (13) was synthesized in our laboratory by solid-phase methods described previously (14).Female Wistar/Furth rats (80-100 g, Harlan SpragueDawley, Indianapolis, IN) were inoculated s.c. in the scapular region with OH3 pituitary tumor cells (obtained from the American Type Culture Collection). The animals were housed 5-7 per cage in a temperature-and light-controlled room. Five to seven animals were used per experimental group. In the first experiment, the treatment with peptides was started before tumors appeared, while in subsequent experiments, peptide administration was initiated when 50-100% of the animals showed well-developed tumors. Tumors were measured weekly with microcalipers and tumor volumes were calculated as described (7). Experiment I. Three days after inoculation of 1 X 106 GH3