Biomedical subjects

C M Townsend

Publications and source records attributed to C M Townsend.

At least 145 records · Page 8Linked to original sources

PubMed1992

Amplification of the HER-2/neu protooncogene in human endocrine tumors.

BACKGROUND: Amplification of HER-2/neu, a protooncogene related to the epidermal growth factor receptor, has prognostic significance in patients with breast cancer. Alterations in protooncogenes have not been determined for endocrine tumors in which prognosis is difficult to predict. We have addressed the question of whether amplification of HER-2/neu or epidermal growth factor receptor occurs in DNA from human endocrine tumor lines and have sought to characterize the HER-2/neu gene and its products in carcinoid tumors of the gut. METHODS: The differential polymerase chain reaction procedure was used to detect genomic amplification in DNA samples from human endocrine tumor cell lines (BON, SIM, STAN) and from paraffin-embedded samples of carcinoid tumors. Sequencing techniques were used to determine whether mutations of the transmembrane domain of HER-2/neu existed. We then further characterized the gene products (RNA and protein) in carcinoid tumors. RESULTS: Amplification of HER-2/neu was identified in all three endocrine tumor cell lines. HER-2/neu amplification was found in four of 10 carcinoid tumors of the gut; three of these four tumors were invasive or metastatic. In addition, HER-2/neu mRNA and protein were expressed in carcinoid tumors. CONCLUSIONS: Amplification of the HER-2/neu protooncogene occurs in endocrine tumors of the gut; quantitation of the actual copy number may be an important prognostic determinant. The unique human endocrine cell lines, established in our laboratory, will be useful models to further examine the significance of alterations of the HER-2/neu gene in endocrine tumors.

Carcinoid Tumor↗

PubMed1992

Bombesin stimulates growth of human gastrinoma.

BACKGROUND: We have previously reported the first establishment and characterization of a functioning human gastrinoma (PT) xenograft. Bombesin, the equivalent of the mammalian gastrin-releasing peptide, has trophic effects on normal and neoplastic tissues of the gastrointestinal tract; the effects of gut hormones on the growth of gastrinoma are not known. The purpose of this study was twofold: (1) to determine the presence of various gut peptides in PT and (2) to determine the effect of bombesin on the growth of PT xenografts. METHODS: PT tumors were examined for expression (mRNA and protein) of various gut peptides by Northern hybridization and immunohistochemistry. In addition, PT xenografts were implanted as 3 mm2 pieces bilaterally subcutaneously in athymic nude mice. Mice were divided into two groups to receive either bombesin (5 micrograms/kg) or saline administered as intraperitoneal injections every 8 hours. Tumor area was measured twice weekly until mice were sacrificed (day 28), when tumor and normal pancreas were removed, weighed, and assayed for DNA and protein content. RESULTS: Both mRNAs and peptides of gastrin and chromogranin A were present in PT tumors. Bombesin significantly stimulated growth of PT tumors from day 18 until mice were sacrificed (day 28). As expected, bombesin stimulated pancreatic growth. CONCLUSIONS: We have demonstrated for the first time that bombesin is a trophic hormone for gastrinoma. The unique cell line PT contains gastrin and chromogranin A and will be a useful model to define the biologic mechanisms controlling the growth of human gastrinomas.

Animals↗

PubMed1992

Cytokine regulation of gut ornithine decarboxylase gene expression and enzyme activity.

BACKGROUND: The enzyme ornithine decarboxylase (ODC) catalyzes the rate-limiting step in polyamine biosynthesis and is important for gut mucosal repair after systemic injury (e.g., burns); however, the mechanisms responsible for the injury-mediated induction of ODC are not known. The purpose of this study was to determine whether interleukin-1 (IL-1) or tumor necrosis factor (TNF), which are released immediately after injury, regulates gut mucosal ODC enzyme activity and gene expression. METHODS: In vivo: In experiment 1, 64 male BALB/c mice received either recombinant IL-1 beta (2 x 10(4) units/kg administered intraperitoneally) or saline solution. In experiment 2, 64 mice received either recombinant TNF-alpha (100 micrograms/kg administered intraperitoneally) or saline solution. We determined ODC enzyme activity and ODC mRNA levels in small intestine and kidneys at 2, 4, 12, and 24 hours after injection. In vitro: We also determined the ODC enzyme activity in intestinal epithelial crypt cells after either IL-1 beta or TNF-alpha treatment. RESULTS: IL-1, but not TNF, increased small intestinal ODC enzyme activity. In addition, IL-1 increased ODC enzyme activity in intestinal epithelial crypt cells at 5 and 6 hours after treatment. Both IL-1 and TNF increased small intestinal ODC mRNA levels. Neither agent affected ODC enzyme activity or ODC mRNA levels in the kidney. CONCLUSIONS: These results suggest that the cytokine-mediated induction of ODC in the small intestine is tissue specific, that the induction occurs at multiple cellular levels, and that ODC may play a vital role in the restoration of gut mucosa that occurs after injury.

Animals↗

PubMed1991

Human carcinoid cell production of paracrine growth factors that can stimulate fibroblast and endothelial cell growth.

A serotonin-secreting human pancreatic carcinoid cell line (BON) is demonstrated to express transcripts for all three mammalian types of transforming growth factor beta (TGF beta 1, 2, and 3). Similarly, freshly excised carcinoid tumors from six patients were also found to express mRNA for all three of the type-beta TGFs. Medium conditioned by BON cells had detectable TGF beta activity, although most of the activity was latent as determined by radioreceptor assay with and without prior acid treatment. However, nonactivated BON-conditioned medium stimulated DNA synthesis, soft agar growth, and an increase in TGF beta 1 and fibronectin mRNA expression in AKR-2B fibroblasts. In addition, BON-conditioned medium had a potent endothelial cell growth-stimulatory activity. Since the TGF beta s inhibit growth of endothelial cells, the presence of other growth factors was suspected. TGF alpha, c-sis, and basic fibroblast growth factor transcripts were also found to be expressed by the BON carcinoid cells. These data indicate that multiple peptide growth factors may have a paracrine role in the desmoplastic reaction accompanying carcinoid tumors.

Amino Acid Isomerases↗

PubMed1991

Expression of cholecystokinin forms by medullary thyroid cancer.

We have studied the production and release of cholecystokinin (CCK) forms by rat medullary thyroid cancer (MTC) in vivo. MTC cells were inoculated s.c. into 8 Wag-Rij rats. One month later, after i.v. injection of calcium plasma levels of CCK, calcitonin and tissue contents of gastrin and calcitonin were determined by radioimmunoassay (RIA), immunocytochemistry, and high-pressure liquid chromatography (HPLC). The tumors were passed 4 times to 8 rats in 1-month intervals fasting levels of CCK in control rats were unaffected by calcium stimulation, and in tumor-bearing rats, plasma CCK was elevated in 3 out of 4 passages, falling to normal levels at the end of passage 4. Hypercalcemia had no effect on plasma levels of CCK in tumor-bearing rats, but did stimulate the release of calcitonin in both control and some tumor-bearing rats in later passages. CCK-8 sulfate was found in all 4 tumor passages but not CCK-33/39. We conclude that rat MTC synthesizes and releases CCK-8, but unlike calcitonin, release of CCK appears unresponsive to calcium stimulation.

Animals↗

PubMed1991

Systemic alterations in ornithine decarboxylase activity caused by colon cancer in mice.

Tumors are known to cause profound changes in host biology, but the mechanisms responsible for these changes remain unclear. Ornithine decarboxylase (ODC) is a rate-limiting enzyme that catalyzes the biosynthesis of polyamines. The purpose of this study was to examine the effects of MC-26 tumor burden on ODC activity in the gastrointestinal tract, kidney and liver of mice. Forty-four Balb/c mice were randomly divided into 2 groups and the test group was pair-fed (to control). Group 1 was the tumor-free control. Group 2 was inoculated subcutaneously with 5 x 10(5) MC-26 cells. The ODC activity in the kidney and liver of tumor-bearing mice was significantly lower compared to tumor-free controls at sacrifice. ODC activity in the colon increased almost 4-fold. These results suggest that the presence of MC-26 tumor causes systemic effects that alter ODC activity. The tumor may elaborate a substance that suppresses ODC activity in some normal tissues while stimulating ODC activity in the tissue from which the tumor was derived.

Animals↗

PubMed1991

Differential sensitivity of various human tumors to inhibition of polyamine biosynthesis in vivo.

Polyamines are essential for normal and neoplastic growth. Ornithine decarboxylase (ODC) is the first and rate-limiting enzyme in the polyamine biosynthetic pathway. alpha-Difluoromethylornithine (DFMO) is an enzyme-activated irreversible inhibitor of ODC, and a known anti-neoplastic agent. The purpose of this study was to examine the susceptibility of various human cancers to inhibition by DFMO in vivo. We have studied three human pancreatic adenocarcinomas, designated CAV, SKI, and PGER, two human colon adenocarcinomas (LS-180 and WIDR), and three metastatic cell lines of a human gastric adenocarcinoma (BHM, BMM, BLM) that were growing in congenitally athymic (nude) Balb/c mice. Mice bearing each tumor were divided into two groups; one group served as controls and the other group received DFMO 3% in drinking water. Tumor growth and weight, and content of DNA, RNA, protein and polyamines were determined and correlated. DFMO significantly inhibited the growth of three of the three gastric tumors, two of the three pancreatic tumors and neither of the two colon tumors. The tumor content of DNA, RNA and protein exhibited a pattern that was parallel to tumor growth. The tumor polyamine concentration did not correlate with sensitivity to DFMO. These findings provide clear evidence for important differences in the sensitivity of various human cancers to growth inhibition by DFMO and indicate that endogenous polyamine levels alone do not predict the sensitivity of the tumors to DFMO.

Adenocarcinoma↗

PubMed1991

Differential effects of sodium butyrate and hexamethylene bisacetamide on growth and secretion of cultured human endocrine tumor cells.

Advanced gastrointestinal endocrine tumors respond poorly to conventional chemotherapy. In this study we examined the effects of two agents that promote cellular differentiation, sodium butyrate and hexamethylene bisacetamide, on the in vitro growth and secretory responses of a human pancreatic carcinoid (BON) and human gastrinoma (PT-2 and PT-SM) cell lines that have been established in our laboratory. We found that both sodium butyrate and hexamethylene bisacetamide strongly inhibited growth of BON, PT-2, and PT-SM cells. With continuous exposure of BON cells to sodium butyrate (2 mmol/L), the doubling time was prolonged, from 60 hours in controls to 156 hours, and saturation density was reduced to 28% that of controls. Hexamethylene bisacetamide (4 mmol/L) reduced saturation density to 37% that of controls in BON cells and prolonged the doubling time, from 60 hours to 103 hours. Antiproliferative effects of similar magnitudes were observed in the gastrinoma cell lines. In contrast, differential effects were produced on amine biosynthesis in BON cells; sodium butyrate stimulated levels of 5-hydroxytryptamine in the cells, whereas hexamethylene bisacetamide caused a profound dose-dependent inhibition of amine biosynthesis. The significant antiproliferative activity of sodium butyrate and hexamethylene bisacetamide and the inhibitory effects of hexamethylene bisacetamide on amine biosynthesis warrant evaluation of these agents or analogues for treatment of metastatic carcinoid and gastrinoma.

5-Hydroxytryptophan↗

PubMed1991

Relationship between glutathione levels and drug or radiation sensitivities in human gastric cancer cell lines in vitro.

Permanent cell lines and clones established from an untreated patient (AGS cells) with gastric carcinoma, and from a similar patient who had been treated with Adriamycin, 5FU and cytoxan (SII cells) were used in a study that compared their drug and radiation survival sensitivities to their glutathidine (GSH) values. The SII parental cell line was more resistant than the AGS cells in vitro to chlorambucil, ACT D, Adria, Bleo, and X-rays. This greater resistance was positively correlated with GSH values that were 1.77 times higher than in the AGS parental cell line. By contrast the SII parental cells were more sensitive than the AGS cells to MeCCNU and Melphalan. The drug and radiation sensitivities expressed among the clones of the two cell lines were heterogeneous and did not correlate with their GSH values.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

Pancreatic regeneration after partial pancreatectomy.

The ability of the pancreas to regenerate and the effects of trophic hormones on regeneration of the pancreas after partial pancreatectomy are not completely understood. We investigated the effects of the trypsin inhibitor FOY-305 (an agent that stimulates endogenous cholecystokinin) on pancreatic regeneration after partial pancreatectomy in rats. FOY-305 or water was administered for either 13 days or 27 days by gavage feeding, after sham operation or partial pancreatectomy (n = 6 to 8 animals per group). FOY-305 stimulated hypertrophy of the pancreatic remnant at 13 days; prolonged treatment for 27 days produced both hypertrophy and hyperplasia. The magnitude of pancreatic growth after FOY-305 administration was significantly greater at 27 days in the pancreatic remnant than growth of the equivalent pancreatic segment (duodenal and parabiliary) in sham-operated rats treated with FOY-305. Our results suggest that endogenous cholecystokinin released by FOY-305 stimulates regeneration after partial pancreatectomy. The pancreatic remnant is more sensitive to trophic stimulation in comparison to the normal pancreas. FOY-305 may be a useful agent in the treatment of pancreatic insufficiency after extensive subtotal pancreatectomy or chronic pancreatitis.

Animals↗

PubMed1991

Establishment and characterization of a human carcinoid in nude mice and effect of various agents on tumor growth.

The authors have established a long-term tissue culture cell line (BON) derived from a metastatic human carcinoid tumor of the pancreas. The cells have been in continuous passage for 46 months. Tissue culture cells produce tumors in a dose-dependent fashion after SC inoculation of cell suspensions in athymic nude mice. BON tumors, grown in nude mice, are histologically identical to the original tumor; they possess gastrin and somatostatin receptors, synthesize serotonin and chromogranin A, and have a doubling time of approximately 13 days. The antiproliferative effects of the long-acting somatostatin analogue, SMS 201-995 (300 micrograms/kg, t.i.d.), and 2% alpha-difluoromethylornithine on BON xenografts in nude mice were examined. Tumor size was significantly decreased by day 14 of treatment with either agent and at all points of analysis thereafter until the animals were killed (day 33). In addition, tumor weight, DNA, RNA, and protein contents were significantly decreased in treated mice compared with controls. Establishment of this human carcinoid xenograft line, BON, provides an excellent model to study further the biological behavior of carcinoid tumors and the in vivo effect of chemotherapeutic agents on tumor growth.

Animals↗

PubMed1991

Specific binding of cholecystokinin, estradiol and somatostatin to human pancreatic cancer xenografts.

We recently reported that human pancreatic cancers differentially respond to the growth inhibitory effects of an estradiol (E2) receptor antagonist, tamoxifen, and a long-acting analogue of somatostatin, Sandostatin. In the present study two human pancreatic cancers, established as xenografts in nude mice, were examined as representative of cancers that respond to either tamoxifen (PGER) or Sandostatin (SKI), for the presence of binding sites for various hormones. Male nude mice were inoculated with either SKI or PGER, by passage of tumor chunks (3 mm2) to the interscapular region. Tumors, obtained from mice after approximately 30 days of in vivo growth, were analyzed for binding to cholecystokinin-octapeptide (CCK), somatostatin and E2, by published procedures, using either crude tumor membranes (CCK), cytosol and nuclear fractions (E2), or cryostat sections of whole tumors (somatostatin). SKI was highly positive for high-affinity (Kd = approximately 1 nM) CCK binding sites at the time of resection with a binding capacity of approximately 1000 fmol/mg protein. With increasing passages, the total number of high-affinity binding sites for CCK, were reduced to non-detectable levels in SKI tumors, while non-saturable binding (Kd = greater than 10 nM) became increasingly evident. Early passages of PGER tumors were similarly positive for high-affinity binding sites for CCK, that steeply declined with increasing passages. Specific binding sites for E2, were observed only in the cytosolic fractions of PGER, with a high binding affinity (Kd = approximately 0.05 nM) and a low binding capacity (15 +/- 3 fmol/mg cytosolic proteins), at all passages examined; E2 binding sites were not detected in cytosolic and nuclear fractions of SKI and in the nuclei of PGER, at all passages. SKI and PGER at different passages were examined for somatostatin binding, and both the early and late passages of PGER were devoid of somatostatin binding sites, while SKI tumors were positive for them. Based on the above results, it appears likely that Sandostatin directly inhibited the growth of SKI tumors, since SKI was positive for somatostatin binding sites; it appears less likely that Sandostatin indirectly mediated its inhibition by attenuating possible stimulatory effects of CCK. Growth inhibitory effects of tamoxifen on PGER were apparently via E2 binding sites, since only the tumors positive for E2 binding sites (PGER) responded to tamoxifen; it remains to be determined if tamoxifen can exert additional effects independent of E2 binding sites on pancreatic cancers.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗

PubMed1991

Somatostatin and analogues in the treatment of cancer. A review.

Somatostatin is a naturally occurring cyclic tetradecapeptide that inhibits release of growth hormone and all gastrointestinal hormones. The beneficial effect of somatostatin in the treatment of certain hypersecretory disorders of hormone excess in well recognized; however its clinical usefulness has been limited in the past by its extremely short plasma half-life. The development of long-acting somatostatin analogues has provided clinically useful agents for treatment of hormone-producing tumors. In addition to well-known inhibiting effects on hormone release and actions, recent studies using experimental tumor models have demonstrated an antiproliferative effect of somatostatin and its analogues on growth of a variety of neoplasms. The exact role of somatostatin analogues in cancer therapy has yet to be established; however studies suggest that these agents could provide a useful and relatively nontoxic adjuvant therapy in the treatment of certain tumors. In this review, the oncologic application of somatostatin and possible mechanism of action are examined and current clinical and experimental studies are summarized.

Breast Neoplasms↗

PubMed1991

Novel therapy for the treatment of human carcinoid.

Development of effective treatment for patients with carcinoid tumors has been hampered by lack of an experimental model. The authors have established the only long-term cell line of a functioning human pancreatic carcinoid tumor (BON) that produces tumors in nude mice. In this study the authors examined the effect of three agents, alpha-interferon (IFN), a somatostatin analog, SMS 201-995 (SMS), and an inhibitor of polyamine biosynthesis, alpha-difluoromethylornithine (DFMO), on the growth of BON tumors. BON was implanted bilaterally as 3-mm2 pieces (subcutaneously [sc]) into male BALB/c nude mice. In the first study, 23 mice were randomized to four groups: control, IFN (1 x 10(6) units, sc, four times a day), IFN + SMS (300 micrograms/kg, intraperitoneally, three times a day), and IFN + 3% DFMO in drinking water. Treatments were initiated on day of tumor implantation. In the second study, mice were randomized to six groups: control, IFN, SMS, DFMO, IFN + SMS, IFN + DFMO, and IFN + SMS + DFMO. Treatments were started on day 15 after tumor implantation. Tumor area and body weights were measured weekly. In both studies mice were killed on day 28 after BON implantation and tumors removed, weighed, and analyzed for DNA and RNA content. In the first study, IFN either alone or in combination with SMS or DFMO suppressed BON tumor growth. When treatment was initiated after established tumor growth (study 2), however, the only effective treatments for suppression of growth of BON were IFN + DFMO and IFN + DFMO + SMS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Expression of neurotensin messenger RNA in a human carcinoid tumor.

Neurotensin (NT), a distal gut peptide, has important regulatory and trophic effects throughout the gut; however the intracellular mechanisms that regulate the gene expression and release of human NT are not known. The purpose of this endeavor was to study a functioning human pancreatic carcinoid cell line (called BON) in vitro that expresses the NT gene, and to study the effect of the cyclic adenosine monophosphate (cAMP) signal-transduction pathway on the expression and release of human NT. RNA was prepared from BON cell line (which has been established in this laboratory); the RNA was analyzed for NT mRNA expression by Northern hybridization with a complementary DNA probe. RNA blot analysis demonstrated that the NT gene is expressed in BON and is transcribed to two mRNAs of 1.0- and 1.5-kb sizes. In the second part of this study, BON cells were treated with either forskolin (FSK), which increases intracellular levels of cAMP, or with serotonin (5-HT), which reduces cAMP in BON cells. Forskolin produced a dose-dependent increase in NT peptide release and, furthermore, FSK (10(-6) mol/L) rapidly increased NT mRNA abundance 1 hour after addition; conversely, 5-HT (10(-5) mol/L) decreased NT mRNA at 1 hour. Neurotensin mRNA levels returned to control values by 3 hours after either FSK or 5-HT, which suggests that the transcript half-life for NT is relatively short. These findings show that the expression and peptide release of human NT is mediated, in part, by the cAMP signal-transduction pathway. Our human carcinoid cell line will provide a useful model to study the in vitro regulation of NT gene expression and peptide release.

Animals↗

PubMed1991

Bacterial translocation and its relationship to visceral blood flow, gut mucosal ornithine decarboxylase activity, and DNA in pigs.

The relationship of bacterial translocation to gut blood flow and mucosal integrity was studied in pigs. Three groups of miniature pigs were studied: sham injured (controls) (n = 7), 50% mechanical reduction in blood flow to the superior mesenteric artery (SMA) and celiac artery (CA) (n = 6), and a 40% third-degree cutaneous flame burn (n = 9). Forty-eight hours after injury, animals were killed and organ samples obtained for analysis. Bacteria of the same biotype as that found in the intestinal lumen were present in the mesenteric lymph nodes (MLN) of 9 of 9 burned pigs and 5 of 6 pigs undergoing partial vascular occlusion. The DNA content and ornithine decarboxylase (ODC) activity were increased in the colon mucosa of animals from both the reduced-flow and burn-injured groups compared with control animals. Decreased blood flow to the gut may contribute to the development of bacterial translocation. In addition, intestinal regenerative capacity remains intact 48 hours after injury.

Animals↗

PubMed1991

Aging and the trophic effects of cholecystokinin, bombesin and pentagastrin on the rat pancreas.

We examined the effect of age on the trophic response of the pancreas to chronic treatment with cholecystokinin (CCK), bombesin, or pentagastrin. Three age groups (3-, 12-, and 24-months) male F344 rats received saline; CCK-8 (5 ng/kg), bombesin (10 micrograms/kg), or pentagastrin (100 micrograms/kg) by intraperitoneal injection t.i.d. for 2 weeks. Rats were then killed and the pancreases excised, weighed, and assayed for DNA, RNA, protein, and polyamine (putrescine, spermidine, and spermine) concentrations and contents. We found that none of the treatments altered body weight at any age. All three hormones increased pancreas size and cell number in 3-month old rats, but by 12 months, all three had increased only pancreatic RNA content. Pancreatic spermidine concentration was decreased by all three hormone regimens in 3- but not in 12-month old rats, and pancreatic putrescine concentration and content were increased in 12-month old rats receiving all three hormones. There was no change in any parameter following any of the three hormones, tested at 24 months of age. We conclude that, at the dosages tested, the trophic response of pancreas to chronic administration of CCK, bombesin, and pentagastrin, which is normally present in young adult rats, is lost with aging.

Aging↗

PubMed1991

Regulation of pancreastatin release from a human pancreatic carcinoid cell line in vitro.

The objective of these experiments was to investigate the influence of activation of three second messenger systems (protein kinase-C, adenylate cyclase-cAMP, and calcium mobilization) on the secretion of pancreastatin (PST) and chromogranin-A (CGA) by a human pancreatic carcinoid cell line (BON) in tissue culture. Stimulation of protein kinase-C by a phorbol ester (0.025-7.5 microM) caused a significant dose-related release of PST (186 +/- 22-4271 +/- 228% over controls). Treatment of BON cells with graded doses of 8-bromo-cAMP (0.14-3.0 mM) and isobutylmethylxanthine (IBMX; 0.01-1.0 mM) also stimulated a dose-related release of PST (107 +/- 22-284 +/- 28 and 16 +/- 12-1076 +/- 100% over controls, respectively). Incubation of BON cells with ionomycin (0.134-13.4 microM) increased the release of PST (102 +/- 15-554 +/- 21% over controls) in a dose-related manner. A combination of IBMX and ionomycin resulted in an additive effect, whereas treatment with a phorbol ester plus IBMX resulted in a synergistic effect on PST release. Pretreatment of BON cells with monensin, an agent that prevents processing of precursors to smaller peptides, significantly decreased PST, but not CGA, secretion in response to phorbol ester or ionomycin. These findings indicate that protein kinase-C, cAMP, and Ca2+ mobilization participate in CGA and PST secretion. Although the observation that secretions of PST and CGA in response to theophylline are quantitatively associated, the absence of a quantitative relationship in the release patterns of PST and CGA in response to phorbol ester and ionomycin do not support a simple precursor-product relationship between CGA and PST. The monensin experiments are consistent with the notion that PST is derived from CGA in BON cells.

1-Methyl-3-isobutylxanthine↗