Biomedical subjects

T Downs

Publications and source records attributed to T Downs.

At least 19 recordsLinked to original sources

PubMed1999

Expression of a foreign protein in human megakaryocytes and platelets by retrovirally mediated gene transfer.

Recent progress in the culture of human megakaryocytes (MKs) has led to the capacity to produce platelets in vitro. This capability enables investigation into the possibility of modifying platelet structure and/or function by genetically altering the MK. To this end, a cDNA for the murine CD9 (mCD9) cell surface protein was introduced into MK progenitors by retrovirally mediated gene transfer and subsequently detected in cultured MKs with a monoclonal antibody (MoAb) that specifically recognizes the murine protein. CD34+ human peripheral blood or marrow progenitors, enriched by immunomagnetic bead selection, were cultured for 5 days in the presence of growth factors, including stem cell factor and thrombopoietin, to induce MK progenitors into the cell cycle. The stimulated cells were then cocultured with the mCD9 retroviral producer cell line for 3 days, followed by culture in serum-depleted medium for 3 to 7 additional days. Flow cytometry analysis using the anti-CD9 MoAb and TAB, a MoAb recognizing human GPIIb, revealed that a large proportion (40-100%) of the MKs expressed mCD9. To ascertain whether these cells were capable of producing mCD9+ platelets, flow cytometry analysis was performed at a time when proplatelets were observed in the culture. mCD9 was detected in up to 59% of the TAB+ platelet-sized particles. Because deteriorating MKs can produce platelet-sized particles in vitro, experiments were performed to determine whether mCD9+ TAB+ particles were functionally active. Addition of phorbol myristate acetate resulted in the redistribution of P-selectin (CD62) from the alpha granule to the platelet surface as detected by MoAbs S12 and G5 in three-color flow cytometry analyses. These studies showed that up to 76% of the mCD9+ TAB+ particles were functionally active. The data show that retrovirally mediated gene transfer is a viable approach for genetically altering MK progenitors, resulting in platelets that express heterologous proteins.

Animals↗

PubMed1999

Use of course-embedded projects for program assessment.

There is increasing demand on science faculty to develop authentic assessment measures for both individual courses and undergraduate programs. We report here on a quarter-long group project used in a neurophysiology course that can be used for either purpose. Small groups of four to five students critically analyze at least 10 articles from the primary scientific literature. The end result of this process is the equivalent of a scientific review article that is presented in two formats, a 10-min oral presentation and a scientific poster presentation. Students perform better on application tasks than on analysis, synthesis, or evaluation tasks associated with the project (P < 0.025) and generally respond positively to process questions (59-82%) but less positively to task questions (36-76%) about group dynamics. The cognitive skills and basic content knowledge required to complete this project are developed throughout the undergraduate program. Thus the project is a type of culminating program experience. However, the project also assesses basic course proficiency, because students cannot analyze primary neuroscience research without an understanding of neurophysiological principles.

Education, Medical, Undergraduate↗

PubMed1998

Expression of catalytically active human cytochrome p450scc in Escherichia coli and mutagenesis of isoleucine-462.

Cytochrome P450scc (P450scc) catalyzes the first step in steroid hormone synthesis, the conversion of cholesterol to pregnenolone. Human P450scc has been poorly studied due to the difficulty of purifying reasonable quantities of enzyme from human tissue. To provide a more convenient source of the human enzyme and to enable structure-function studies to be done using site-directed mutagenesis, we expressed the mature form of human P450scc in Escherichia coli. The expression system enabled us to produce larger quantities of active cytochrome than have previously been isolated from placental mitochondria. The expressed P450scc was purified to near homogeneity and shown to have catalytic properties comparable to the enzyme purified from the human placenta. The mature form of human adrenodoxin was also expressed in E. coli and supported cholesterol side chain cleavage activity with the same Vmax as that observed using bovine adrenodoxin but with a higher Km. Mutation of Ile-462 to Leu in human P450scc caused a decrease in the catalytic rate constant (kcat) with cholesterol as substrate, increased the Km for 22R-hydroxycholesterol, but did not affect the kinetic constants for 20 alpha-hydroxycholesterol. This suggests that Ile-462 lies close to the side chain binding site and that the side chains of cholesterol, 22R-hydroxycholesterol, and 20 alpha-hydroxycholesterol occupy slightly different positions in the active site.

Animals↗

PubMed1998

Assessing the burden of cancer in Texas using vital statistics data.

BACKGROUND: Vital statistics data were used to describe the burden of cancer in Texas. METHODS: Average annual age-adjusted mortality data in Texas (1986 to 1990) for 17 cancer types were compared with the US data for whites and blacks and with California data for Hispanics. Trends were examined from 1980 to 1990 for the entire state and from 1976 to 1989 for 24 geographic regions within the state. RESULTS: Mortality excesses were detected for lung and liver cancer, and deficits for colorectal, breast, and prostate cancers. Rates were generally stable from 1980 to 1990 with several exceptions (lung, liver, colon). Six areas of Texas, including four areas along the Gulf Coast, had relatively more excesses of various cancers, without a discernible pattern by cancer type. CONCLUSIONS: Overall, Texas has fared favorably in cancer mortality when compared with the United States. Enhanced evaluation of the frequency of cancer, as well as the conduct of etiologic research, must await the availability of statewide long-term cancer incidence data.

Black or African American↗

PubMed1998

A cancer risk model with adaptive repair.

The cancer risk model described herein first appeared in 1982. The model provides a plausible mechanism with biological underpinnings that might reasonably explain observed phenomena in cancer dose-response studies that are not being addressed by the risk models currently in use. This article is a summary and explanation of the features of the model that relate to hormesis. Data from several saccharin studies served in large part to motivate the original research, and were used to illustrate beneficial low-dose effects that could be explained by the model. The model itself is a function of linear ratios of the administered dose x. Linear ratios arise naturally from non-linear Michaelis-Menten kinetics, as described in the next section. The one-hit cancer risk model is used to illustrate the hormetic concepts brought out by linear ratios. The one-hit model is modified to account for repair and for non-linear kinetics, by using a linear ratio of the administered dose instead of the actual administered dose, and by expressing the probability that a 'hit' is repaired as a linear ratio of the administered dose. The phenomenon of hormesis - or low-dose beneficial effects-has been widely observed and accepted. Yet none of the cancer risk models currently in wide use have attempted to accommodate hormetic effects. The modified one-hit model developed herein does not attempt to account for elimination or detoxification, but nevertheless it provides plausible explanations for certain classes of observed hormetic phenomena associated with experimental testing of carcinogenic substances in animals.

Adaptation, Physiological↗

PubMed1998

Delayed-interval delivery in a quadruplet pregnancy after intrauterine death of a partial molar pregnancy and preterm delivery. A case report.

BACKGROUND: Delayed-interval delivery is infrequent in twin gestation and more rare in triplet and quadruplet gestation. Coexistence of a triploid pregnancy with a normal fetus has not previously been reported to have resulted in survival of the normal fetus. CASE: A 26-year-old woman, gravida 2, para 0-0-1-0, was diagnosed with a quadruplet pregnancy. At 16 1/2 weeks' gestation she developed preeclampsia and severe hyperemesis. Ultrasound was consistent with partial molar pregnancy in quadruplet D. Quadruplet D died in utero, and the preeclampsia and hyperemesis resolved. At 19 5/7 weeks, spontaneous rupture of the membranes and preterm labor occurred, and quadruplet A, stillborn female weighing 260 g, was delivered. With the use of antibiotic therapy, tocolysis and bed rest, the remaining two fetuses were maintained in utero until 32 6/7 weeks' gestation, when quadruplet B, a 1,470-g female, and quadruplet C, a 1,700-g female, were delivered. CONCLUSION: This was the first reported case of surviving fetuses coexisting with a partial molar pregnancy. This case was also complicated by preterm delivery and successful delayed-interval birth in a quadruplet pregnancy.

Adult↗

PubMed1997

Erythropoietin potentiates thrombus development in a canine arterio-venous shunt model.

Erythropoietin (EPO) has been previously shown to affect platelet as well as red cell production. In addition, recent studies demonstrated that platelets from EPO-treated dogs are hyperreactive towards thrombin when compared to age-matched, control platelets. This report extends these observations by quantitating the thrombogenic potential of EPO in dogs. Dogs with arterio-venous (A-V) shunts received 100 U EPO/kg/day for 6 days, and thrombogenicity was serially monitored by insertion of a thrombotic surface into the A-V shunt. The resulting experimental thrombi were analyzed for platelet and erythrocyte content after formalin-fixation and chymotrypsin digestion, a technique which allows non-isotopic quantitation of cellular components. By day 5 of EPO-administration all animals demonstrated a significant increase in platelet and red cell content of the experimental thrombi; the average increase in platelet number was 2.94 +/- 0.12 fold (mean +/- 1 SE; n = 3; p = 0.006) above baseline while that for red cells was 2.46 +/- 0.18 fold above baseline (p = 0.023). After cessation of EPO, thrombogenicity returned to normal. During EPO-treatment, the percentage of thiazole orange-positive (TO+) platelets increased significantly to 17.2 +/- 1.6% (mean +/- 1 SE; n = 3) on day 5 compared to a pre-treatment level of 8.5 +/- 0.9% (p = 0.029). Although the percentage of TO+ erythrocytes also increased during the short course of EPO administration, the change was not significant. Despite the increases in TO+ cells, total platelet and erythrocyte counts did not change significantly within the time frame of these experiments. Fibrin/fibrinogen content of the experimental thrombi was unaltered with EPO-treatment. These data demonstrate that human EPO is pro-thrombotic in dogs and, in conjunction with earlier studies, suggest that hyperreactive platelets may be responsible for the potentiated thrombogenicity.

Animals↗

PubMed1997

Cancer mortality among petroleum refinery and chemical manufacturing workers in Texas.

Epidemiologic historical cohort studies of petroleum refinery and chemical manufacturing workers in Texas were reviewed to examine their cancer mortality in comparison to the U.S. and to assess the possible impact of cancer mortality among these workers on the State of Texas as a whole. Summary standardized mortality ratios and 95% confidence intervals were calculated for 20 cancer types, taking into account the heterogeneity of individual studies. There were 4314 cancer deaths among the 92,318 workers employed in 10 independent plant populations. Overall, there was a significant deficit in cancer mortality among petrochemical workers compared with the general U.S. population (SMR = 88, 95% CI = 80 to 96). Only the summary SMRs for brain cancer (SMR = 113, 95% CI = 96 to 133) and leukemias (SMR = 112, 95% CI = 94 to 130) approached statistical significance. Lung and liver cancer mortality excesses, noted for Texas as a whole, were decreased in these workers. Additional follow-up of these cohorts, their expansion to include minority and female workers, and additional study of possible occupational contributions to leukemia and brain cancer are recommended.

Chemical Industry↗

PubMed1996

Relative reactivity of platelets from thrombopoietin- and interleukin-6-treated dogs.

Previous reports have shown that interleukin-6 (IL-6) enhances the responsiveness of platelets to thrombin stimulation and has modest thrombocytopoietic effects in vivo. Thrombopoietin (TPO; mpl ligand) has been shown to have dramatic thrombocytopoietic effect in vivo, but little is known of its capacity to alter platelet function. In this study, a direct comparison of the effects of IL-6 and TPO on platelet function in dogs has been performed, with modest doses of TPO (1 microgram/kg/d) chosen to match or moderately exceed the platelet counts achieved with IL-6 (40 micrograms/kg/d) for 10 days. Platelet responsiveness to thrombin stimulation was assessed in TPO-treated, IL-6-treated, and control dogs by flow cytometric measurement of P-selectin expression. On day 5, the dose of thrombin promoting half maximal stimulation (EC50) of platelets was not significantly changed in TPO-treated dogs, whereas in IL-6-treated dogs the EC50 decreased to 73.1% +/- 6.1% (mean +/- 1 SD; n = 5) of control values (P < 0.01). These experiments were performed on both gel-filtered platelets and washed whole blood, indicating that the observed changes in EC50 were caused by cytokine-mediated alteration of platelets rather than plasma components. Because it has been shown that thiazole orange specifically labels a subpopulation of dog platelets that is less than 24 hours old, the thrombin responsiveness of these young, newly synthesized platelets was determined. The EC50 of thiazole orange-positive platelets from IL-6-treated dogs decreased dramatically by day 5 to 46.5% +/- 13.1% (n = 4) of control values (P < 0.001), whereas TPO-treated dogs did not significantly change. When TPO was directly incubated with platelets ex vivo, no effects on either thrombin-mediated P-selectin expression or adenosine diphosphate-induced fibrinogen binding were observed. These data show that IL-6 alters platelet function, as measured by reactivity to thrombin, whereas TPO does not. This divergence in function is observed even though TPO is equally, or more, effective at promoting platelet production under these experimental conditions.

Adenosine Diphosphate↗

PubMed1996

Cytokine-induced alteration of platelet and hemostatic function.

A number of nonplatelet-specific cytokines that augment platelet recovery following chemo/radiotherapy have been described. The members of the interleukin 6 (IL-6) family have properties that influence the hematopoietic system beyond their modest thrombocytopoietic effects. Studies performed in a canine model with IL-6 have shown that this factor augments plasma fibrinogen and von Willebrand factor (vWf) concentrations and decreases the level of free protein S. IL-6 appears to decrease the bleeding time in thrombocytopenic dogs, although this effect does not seem to be due to a direct influence of the factor on endothelial vWf or tissue factor production. The factor does not directly alter platelet function in vitro, but when administered to dogs, it increases the sensitivity of the platelets to activation by thrombin. Normal platelets injected into IL-6-treated dogs, and platelets from IL-6-treated dogs injected into normal animals, survive normally. Following injection of either IL-6 or the more specific thrombocytopoietic cytokine thrombopoietin (TPO), IL-6 increases platelet responsiveness to thrombin-induced activation to a greater extent than does TPO. The data show that IL-6 has certain properties that might be construed as prohemostatic, and these properties may prove to be useful clinically.

Animals↗

PubMed1996

Inhibition of the acute-phase response in vivo by anti-gp130 monoclonal antibodies.

The acute-phase response is believed to be an important systemic defence reaction to inflammation during infection, trauma, injury or neoplasia. Although the interleukin-6 (IL-6) family of cytokines appear to be the major regulators of the acute-phase reaction, the exact biological significance of this process remains unknown. In this study, a panel of monoclonal antibodies (Mabs) was raised against the extracellular domain of human gp130 (the common signal transducing chain of the IL-6 cytokine family) in order to inhibit the biological activity of IL-6-like cytokines in vivo. Mabs designated 4B11 and 2H4 were most effective in the inhibition of the in vitro acute-phase response on hepatoma cells and prevented the IL-6-induced growth inhibition of A375 cells. Administration of the antibodies to dogs at a dosage of 8 mg/kg/d showed that 2H4 was a potent inhibitor of the IL-6-induced (40 micrograms/kg/d) acute-phase response, abrogating IL-6-mediated increments in fibrinogen, C-reactive protein and the platelet count. This antibody, the first described to abrogate the acute-phase response in vivo, may not only permit development of a new anti-inflammatory strategy, but provides an excellent tool for defining the function of acute-phase proteins in inflammation and infection.

Acute-Phase Reaction↗

PubMed1994

A survey of actinic keratoses among paraquat production workers and a nonexposed friend reference group.

Follow-up on two reports of an excess of keratoses among paraquat production workers was conducted to evaluate the contribution of occupational exposures to the prevalence of keratoses among workers in a paraquat production plant in Texas. A cross-sectional study design was used to compare the prevalence of keratoses among current workers to an age, race, and sex frequency-matched group of their friends who had never worked at the plant. The analysis is based on 112 workers and 232 friends. Exposure, outcome, and covariables used in the analyses were obtained from an interview questionnaire, dermatology exam, and company records. Overall, the prevalence proportion of the presence of any actinic keratoses among workers and friends was similar (0.30 and 0.28, respectively). Among high cumulative exposed workers, the prevalence of any actinic keratoses was 0.40 compared to 0.20 among low-exposed workers and 0.28 among friends. These results were further explored using a multiple logistic regression approach to adjust for known risk and possibly confounding variables. Statistically significant high risks of actinic keratoses were demonstrated for freckling before age 16 years, older age, suntanning behaviors, occupational exposure to polycyclic aromatic hydrocarbons (PAH), and Fitzpatrick skin type. There was no significant contribution of overall exposure status (worker vs. friend). Similar to the crude analysis, the odds of actinic keratoses of high-exposed workers compared to friends was 1.9 (confidence interval [CI] = 0.9-4.2) whereas the comparable odds ratio for low-exposed workers vs. friends was 0.6 (CI = 0.2-1.7). These data do not demonstrate an excess of actinic keratoses overall nor any consistent increase in the odds of keratoses with an increase in plant exposure level.

Adult↗

PubMed1992

Thrombocytopoiesis in normal and sublethally irradiated dogs: response to human interleukin-6.

The response of megakaryocytes and platelets to the administration of recombinant human interleukin-6 (IL-6) was investigated in normal and sublethally irradiated dogs. IL-6 was administered for 2 weeks at doses of 10 to 160 micrograms/kg/d to normal animals to assess dose-response and toxicity. Subsequently, 40, 80, or 160 micrograms/kg/d for 2 weeks was administered to animals treated with 200 cG total body irradiation. Analysis of normal dogs showed a significant increment in the platelet count detectable approximately 11 days after initiation of IL-6 at all administered doses. Large platelets greater than 6.3 microns in diameter were observed 1 day after beginning IL-6, progressively increasing to as many as 19.1% of the total circulating platelets by day 10. The ploidy distribution of the marrow megakaryocytes did not differ from the normal at doses of less than or equal to 80 micrograms/kg/d, but at 160 micrograms/kg/d, a shift toward higher ploidy cells was noted. No change in total white count was noted; however, a decrease in hematocrit was seen at all doses. In the irradiated animals, the platelet count recovered earlier in the IL-6-treated dogs than in the controls, but no consistent change in the ploidy distribution was observed irrespective of dose. Large platelets were also noted in the treated animals, comprising up to 6.9% of the total platelet count. Fibrinogen levels were elevated to greater than 4 times normal. A significant decrease in hematocrit was seen in all animals, while no consistent change was noted in the white count. Elevations in serum cholesterol, triglycerides, and alkaline phosphatase, together with a decline in serum albumin were observed in all the treated animals (both normal and irradiated), but clinical symptoms were observed only in the dogs receiving greater than or equal to 80 micrograms/kg/d. The data show that IL-6 alone is capable of enhancing platelet recovery in dogs with bone marrow suppression.

Animals↗

PubMed1992

Characteristics of a novel rat anti-mouse platelet monoclonal antibody: application to studies of megakaryocytes.

Using murine platelets as an immunogen, a rat monoclonal antibody (designated 4A5) that recognizes only murine blood platelets and marrow megakaryocytes was developed. The extent of binding of 4A5 to platelets was dependent upon their state of activation. Following phorbol ester, ionophore, or thrombin stimulation of resting platelets, a decrease of > 50% in the binding of 4A5 was observed by flow cytometry. This decrease in antibody binding to the platelets was accompanied by an increase in antibody released into the platelet-free supernatant following platelet activation. When platelets were first radioiodinated, followed by activation and incubation of the platelet-free supernatant with 4A5-derivatized beads, no precipitable counts were observed compared with control resting platelets. This suggests that antibody release was related to an activation-dependent conformational change in the 4A5 epitope. Following solubilization of biotinylated platelets, 4A5 bound to an 80-kd membrane protein. Immunohistochemical studies with 4A5 showed that megakaryocytes could be identified both in vitro and ex vivo. When marrow was first stained histochemically with 4A5 followed by staining for acetylcholinesterase, the distribution of stained cells was similar. Flow cytometric analysis using 4A5 and propidium iodide showed that the antibody could be used to identify megakaryocytes for ploidy analysis in vivo or in vitro. 4A5 was capable of inducing a moderate thrombocytopenia in mice compared with polyclonal anti-platelet serum. When bound to plastic or to magnetic beads, 4A5 could be used to purify murine megakaryocytes to homogeneity. The data suggest that monoclonal antibody 4A5 will be useful in quantitative studies of murine platelets and megakaryocytes.

Animals↗

PubMed1991

Interleukin-6 mRNA and protein increase in vivo following induction of acute thrombocytopenia in mice.

Induction of experimental thrombocytopenia in rodents results in the enhancement of megakaryocytic growth and differentiation. Interleukin-3 (IL-3) and IL-6, cytokines with a broad spectrum of biologic activities, stimulate megakaryocytopoiesis in vitro. To determine if expression of these factors might increase in response to experimental thrombocytopenia, we measured steady-state levels of IL-3 and IL-6 mRNA following rabbit antiplatelet serum (APS) injection. Groups of mice were injected intravenously with 0.2 mL APS while control animals received rabbit antilymphocyte serum (ALS), normal rabbit serum (NRS), or phosphate-buffered saline (PBS). At various times up to 72 hours after injection mice were exsanguinated and splenectomized. Platelet counts in the experimental animals were less than 12% of controls. Splenic RNA was hybridized in solution to 32P-UTP-labeled cRNA probes for IL-3 and IL-6. RNase-resistant hybrids were resolved on denaturing gels and visualized autoradiographically. IL-3 hybrids were undetectable at all time points tested, irrespective of the film exposure time or specific activity of the probe. Conversely, IL-6 hybrids were easily visualized and showed peak expression at 1.5 to 2.0 hours. By 3 hours, IL-6 mRNA had returned almost to the level of the controls. Similar results were observed in the bone marrow, although maximal IL-6 mRNA in that tissue was observed 4 hours following APS administration. To determine if this mRNA increment was associated with a concomitant increase in bioactive protein, serum was tested for its ability to stimulate IL-6-dependent B9 cells. At 1.75 hours following injection, experimental animals showed a small but significant increment in IL-6 activity compared with controls (200 +/- 30 U/mL IL-6 compared with 129 +/- 17 U/mL in ALS-injected controls, 106 +/- 17 U/mL in NRS-injected controls and 84 +/- 17 U/mL in PBS-injected controls). The data show that IL-6 mRNA and bioactive protein increase in response to acute immunothrombocytopenia, while no increment in IL-3 is detectable. These results suggest that IL-6 may play a role in the physiologic response to acute immunothrombocytopenia.

Acute Disease↗

PubMed1991

Canine megakaryocytopoiesis: analysis utilizing a monoclonal antibody to a 140-kd dog platelet protein.

The dog, a convenient and relatively large animal whose size permits repetitive blood and marrow sampling, marrow biopsy, and mechanical apheresis, would be a suitable experimental model for the study of in vivo megakaryocytopoiesis. A monoclonal antibody to a 140-kd dog platelet membrane protein has been developed that reacts with canine megakaryocytes. Using the fluoresceinated derivative of this antibody to identify megakaryocytes and propidium iodide staining to measure relative DNA content, the DNA distribution of megakaryocytes in dog bone marrow or in cultured dog marrow cells could be rapidly assessed by flow cytometry. Normal dogs showed a modal ploidy of 16N (54%), with 17% 8N and 16% 32N. In contrast, dogs made thrombocytopenic by plateletpheresis showed a shift in distribution to higher ploidy cells (36% 32N). The data show that use of a specific marker of megakaryocytes in combination with flow cytometric analysis is an accurate and reproducible method of assessing megakaryocytopoiesis in a convenient and easily manipulable animal model.

Animals↗

PubMed1988

Medical management of acromegaly due to ectopic production of growth hormone-releasing hormone by a carcinoid tumor.

A 59-yr-old woman with a disseminated carcinoid tumor was evaluated for acromegaly. She had previously undergone a hypophysectomy for acromegaly and an enlarged pituitary, with a reduction in her serum GH levels from 100 to 4 micrograms/L. Recurrence of acromegalic symptoms 2 yr later was accompanied by elevated serum GH (16 micrograms/L) and insulin-like growth factor I (IGF-I; 528 micrograms/L) and plasma GHRH levels (12 micrograms/L; normal, less than 30 ng/L). Computed tomographic scan did not reveal pituitary enlargement. Metastatic carcinoid tissue in bone removed at biopsy contained GHRH (100 pg/mg tissue). High performance liquid chromatography of plasma GHRH revealed predominantly GHRH-(3-40)-OH, a biologically inactive GHRH metabolite, along with mature GHRH forms, while carcinoid tissue contained both GHRH-(1-40)-OH and GHRH-(1-44)-NH2. Treatment with pergolide initially resulted in reduction in serum GH and IGF-I levels and amelioration of symptoms of acromegaly. However, after 14 months of pergolide therapy, serum GH levels increased despite administration of up to 1000 micrograms pergolide/day. Plasma GHRH levels remained elevated throughout the treatment period. Subsequent treatment with SMS 201-995, a long-acting somatostatin analog, for over 1 yr resulted in sustained reductions of ectopic GHRH secretion, GH hypersecretion, and IGF-I levels. Plasma GHRH levels correlated with simultaneously measured serum GH levels in response to acute SMS 201-995 administration. SMS 201-995 was an effective medical treatment for acromegaly caused by ectopic GHRH production in this patient.

Acromegaly↗

PubMed1986

Mitotic inhibition and aneuploidy induction by naturally occurring and synthetic estrogens in Chinese hamster cells in vitro.

We used a predominantly diploid Chinese hamster cell line to test a number of naturally occurring and synthetic estrogens for their ability to arrest cells at metaphase, their potential for allowing anaphase recovery, and their capability of inducing aneuploid progeny. The chemicals employed included diethylstilbestrol, dienestrol, hexestrol, beta-estradiol, ethynylestradiol and estriol. We also tested progesterone, estrone and testosterone in this regard. Only estrogens and their synthetic analogs caused mitotic arrest and aneuploidy, while progesterone, estrone and testosterone did not cause mitotic disturbances. Among the estrogens, DES was the most effective arrestant on a comparative molar basis, whereas dienestrol was most potent over a wide range of concentrations. Estriol was the least potent as an arrestant but was an effective inducer of aneuploidy. The addition of a metabolic activator (S9) did not alter the ability of DES to arrest mitosis. Following the removal of the drugs, cells were able to quickly reorganize a spindle apparatus and enter anaphase. Diethylstilbestrol, dienestrol, hexestrol, beta-estradiol, ethynylestradiol and estriol caused significant increase in aneuploidy within a narrow range of high concentrations in recovering cell populations. Aneuploidy was induced in a non-random manner. Immunofluorescence studies with anti-tubulin antibody indicate that estrogens may have a mechanism of mitotic arrest similar to that of colchicine and colcemid, viz inhibiting the polymerization of tubulin to form microtubules. These data suggest that the interaction between estrogens and microtubules may mediate the induction of aneuploidy in somatic cells. Aneuploidy induction by DES and similar compounds may be related to their carcinogenic potential.

Anaphase↗