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Biomedical subjects

S Sandler

Publications and source records attributed to S Sandler.

At least 181 records · Page 10Linked to original sources
PubMed1985

A randomized study of low and high doses of leukocyte alpha-interferon in metastatic renal cell carcinoma: the American Cancer Society collaborative trial.

A prospective randomized trial of low versus high doses of human leukocyte alpha-interferon (1 X 10(6) units/day for 28 days versus 10 X 10(6) units/day for 28 days) was carried out in 30 patients with metastatic renal cell carcinoma, to test the tolerance and relative antitumor effects of these interferon doses. Both doses were tolerated well, and responses to the human leukocyte alpha-interferon were observed overall in seven individuals, including complete, partial, and minimal tumor regressions. Six of the seven responses occurred in patients who received the high dosage, and three of these responses were major responses. While not statistically significant, this result suggested a dose-response relationship. One minimal response was observed in a patient treated at low dosage. Nine individuals who were stable after 1 month of therapy at low dosage were randomized to a further month of therapy at low or high dosage, during which one of four at high dosage had a partial response, and none of five at low dosage manifested response. Regression of pulmonary disease in one individual was delayed, occurring 3 months after therapy at the high dose and enduring for a period of 28 months. Major objective responses in other patients were of 4 and 15 months duration. Human leukocyte alpha-interferon is an active agent in renal cell carcinoma at the dosage of 10 million units daily. No relationship of toxicity to response was evident in this trial. Optimum dosage and duration of treatment have yet to be established.

Adenocarcinoma↗
PubMed1984

Protection by dimethyl urea against hyperglycaemia, but not insulitis, in low-dose streptozotocin-induced diabetes in the mouse.

The protective effect of dimethyl urea, a hydroxyl radical scavenger, against low-dose streptozotocin-induced diabetes has been evaluated. Dimethyl urea was given to C57BL/KsJ mice before five daily injections of streptozotocin. The saline pre-treated control animals became gradually hyperglycaemic, whereas the dimethyl urea treated group remained normoglycaemic during the 11 week follow-up period. Two weeks after the first streptozotocin injection, six out of ten dimethyl urea-treated and 12 out of 15 saline-treated mice had insulitis. Four or 11 weeks after the streptozotocin treatment, insulitis was rare in both groups. Multiple injections of dimethyl urea only did not affect the serum glucose concentrations or the islet morphology. It is suggested that dimethyl urea protected against hyperglycaemia by reducing the beta-cell cytotoxic effects of the low doses of streptozotocin. An increased number of cells would thus be preserved and the animals less prone to develop diabetes, despite the presence of an inflammatory process in the pancreatic gland.

Animals↗
PubMed1984

Long-term effects of cyclosporin A on cultured mouse pancreatic islets.

In the light of recent attempts to treat newly-diagnosed Type 1 (insulin-dependent) diabetic patients with cyclosporin A, and reports suggesting an impaired glucose tolerance following immunosuppression therapy with cyclosporin A, we investigated the long-term effects of cyclosporin A on islet beta-cell morphology and function in vitro. Collagenase-isolated mouse pancreatic islets were cultured free-floating for 7 days in medium RPMI 1640 + 10% calf serum in the presence of cyclosporin A (0.1 or 1.0 mg/l). Islets cultured in the presence of the higher cyclosporin A concentration had impaired islet proinsulin biosynthesis and insulin release when challenged with high glucose concentration. Moreover, the insulin content of the drug-exposed islets was decreased and so was the rate of DNA synthesis. The glucose oxidation and respiratory rates, however, remained unaffected, suggesting that the impaired insulin production was not a result of defective oxidative metabolism. There were no changes in the ultrastructure or phospholipid biosynthesis of the islets after the drug treatment. These data indicate that cyclosporin A affects islets in culture, the clinical implications of which are so far difficult to assess. The inhibitory effect of cyclosporin A on islet cell DNA synthesis must nevertheless be considered in attempts to ameliorate Type 1 (insulin-dependent) diabetes, and when grating islet cells in numbers primarily insufficient to cure the recipient.

Animals↗
PubMed1984

The significance of culture for successful cryopreservation of isolated pancreatic islets of Langerhans.

It was the aim of the present study to investigate the significance of culture before and after freeze-thawing of isolated mouse pancreatic islets. To evaluate the impact of culture before freezing (5 degrees C/min; 2 M dimethyl sulfoxide), islets were frozen either directly after isolation or after 2, 4, or 7 days of culture in medium RPMI 1640. The culture period after thawing was 7 days. Islets immediately frozen exhibited virtually no (pro)insulin biosynthesis and also a severe inhibition of glucose-stimulated insulin release. The precultured (2-7 days), frozen islets synthesized and released insulin at rates comparable to those of nonfrozen, cultured islets. Studies of the effects of culture after freeze-thawing were performed after a 3-day culture period prior to freezing. The (pro)insulin biosynthetic rates did not differ between islets cultured for 0-7 days after thawing. There was an apparent increase of glucose-stimulated insulin release when the islets were cultured for more than 2 days after thawing. It may be that the decreased viability of islets frozen immediately after isolation was due to minor cell damage induced by the collagenase incubation. During culture the islets may recover and become more resistant to freeze-damage. The beneficial effect of culture after thawing may reflect the loss of damaged cells, which otherwise would influence the results of the viability tests.

Animals↗
PubMed1984

Survival of human fetal pancreatic explants in organ culture as reflected in insulin secretion and oxygen consumption.

Human fetal pancreatic explants were maintained in organ culture for up to 12 days in medium TC 199 or RPMI 1640 supplemented with 20% fetal calf serum. The explants were cultured at their air-liquid interface on a Millipore filter supported by surgical gel foam (ALI technique). The insulin accumulation in the culture medium decreased considerably when explants were maintained for 6 days in RPMI 1640. No corresponding decline was observed with medium TC 199. Four out of 9 RPMI 1640-cultured and 8 out of 11 TC 199-cultured explants responded with an increased insulin release when challenged with high glucose-plus-theophylline after one week of culture. With these explants there was a statistically significant correlation between their rates of respiration and insulin secretion. Furthermore, significant correlations were found between the fetal crown-heel length on the one hand--and the insulin content, insulin response, and oxygen uptake on the other--of the TC 199 cultured explants. There was no apparent change in the rate of insulin accumulation by addition of high glucose or amino acids to the TC 199 medium. It is concluded that oxygen uptake measurements, requiring only minute amounts of tissue, are useful for assessing the viability of human fetal pancreatic explants, and that the ALI technique for maintaining human fetal pancreas in culture offers no obvious advantage over that of the submersion technique. There is also evidence that suggests a better functional preservation in culture medium TC 199 than in RPMI 1640.

Fetus↗
PubMed1984

Multiple low-dose streptozotocin-induced diabetes in the mouse. Evidence for stimulation of a cytotoxic cellular immune response against an insulin-producing beta cell line.

Mice were examined for the presence of splenocytes specifically cytotoxic for a rat insulinoma cell line (RIN) during the induction of diabetes by streptozotocin (SZ) in multiple low doses (Multi-Strep). Cytotoxicity was quantitated by the release of 51Cr from damaged cells. A low but statistically significant level of cytolysis (5%) by splenocytes was first detectable on day 8 after the first dose of SZ. The cytotoxicity reached a maximum of approximately 9% on day 10 and slowly decreased thereafter, becoming undetectable 42 d after SZ was first given. The time course of the in vitro cytotoxic response correlated with the degree of insulitis demonstrable in the pancreata of the Multi-Strep mice. The degree of cytotoxicity after Multi-Strep was related to the number of effector splenocytes to which the target RIN cells were exposed and was comparable to that detectable after immunization by intraperitoneal injection of RIN cells in normal mice. The cytotoxicity was specific for insulin-producing cells; syngeneic, allogeneic, and xenogeneic lymphocytes and lymphoblasts, 3T3 cells, and a human keratinocyte cell line were not specifically lysed by the splenocytes of the Multi-Strep mice. This phenomenon was limited to the Multi-Strep mice. Splenocytes from mice made diabetic by a single, high dose of SZ exhibited a very low level of cytotoxicity against the RIN cells. The cytotoxic response was also quantitated in splenocytes from control and Multi-Strep mice (10 d after the first dose of SZ) before and after culture with mitomycin-treated RIN cells in the presence of T cell growth factor (TCGF). The cytotoxicity of the Multi-Strep splenocytes was enhanced more than fivefold after such culture, suggesting the proliferation of an effector cell that could be stimulated and supported in vitro by TCGF. These results support the hypothesis that cell-mediated anti-beta cell autoimmunity may play a role in the destruction of the beta cells in this animal model. The stimulation of this response by TCGF may provide a tool by which enough cytotoxic effector cells could be obtained to establish their possible direct pathogenetic role in the induction of insulin-dependent diabetes. In addition, such cells will be a valuable tool to define the specific beta-cell antigens that may direct the highly selective cell-mediated destruction of these cells in experimental models and, perhaps, in human insulin-dependent diabetes mellitus.

Adenoma, Islet Cell↗
PubMed1984

Nicotinamide does not protect islet B-cell metabolism against alloxan toxicity.

Nicotinamide, a poly(ADP-ribose)synthetase inhibitor, protected NMRI mice against alloxan-induced hyperglycemia when given 10 min before, but not 10 min after, the injection of the drug. Pretreatment in vivo with nicotinamide induced hyperglycemia at the time of alloxan injection, and this could account for the protective action of nicotinamide against alloxan diabetes. Exposure of islets to alloxan (2 mM) in vitro caused a marked inhibition of both glucose-stimulated proinsulin biosynthesis and insulin release, and this was not affected by the action of nicotinamide. Alloxan-impaired islet glucose oxidation was partly restored by nicotinamide. The decreased islet content of NADH plus NAD, which was observed after alloxan treatment, could be prevented by nicotinamide. Glucose-stimulated islet oxygen uptake was abolished after treatment with alloxan, and nicotinamide had no protective effect in this process. Leucine (10 mM) plus glutamine (10 mM), however, were still able to evoke an islet respiratory response after alloxan exposure. Alloxan caused an immediate increase in the islet efflux of radiolabeled nucleotides, which was followed after about 5 min by a further increase. This latter increase of the radio efflux was inhibited by the addition of nicotinamide. The inability of nicotinamide to prevent the alloxan-induced impairment of proinsulin biosynthesis, insulin release, and oxygen uptake, together with the failure of nicotinamide to prevent the development of diabetes when given after alloxan, does not support a current hypothesis that the major cytotoxic effect of alloxan is primarily due to DNA damage. The present data suggest that organelles other than the nuclei, e.g., the mitochondria or the plasma membrane, are the primary sites of B-cell injury by alloxan.(ABSTRACT TRUNCATED AT 250 WORDS)

Alloxan↗
PubMed1984

Doxorubicin and cisplatin for recurrent or metastatic squamous cell carcinoma of the head and neck.

Thirty-six patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with doxorubicin and cisplatin. The overall response rate (complete + partial) was 30%, with a median duration of response of 4 months. Median survival durations for responders and nonresponders were 15 and 4 months, respectively. Nausea, vomiting, and alopecia were common. Neither grade 4 myelosuppression nor irreversible renal failure was observed.

Adult↗
PubMed1983

Streptozotocin, but not alloxan, induces DNA repair synthesis in mouse pancreatic islets in vitro.

In the present investigation, the abilities of streptozotocin and alloxan to induce DNA repair synthesis in isolated mouse pancreatic islets have been compared using an autoradiographic technique. Streptozotocin exposure in vitro induced a dose-dependent DNA repair synthesis, whereas no such effect was observed after alloxan treatment. The hydroxyl radical scavenger dimethyl urea and the poly(ADP-ribose) synthetase inhibitors nicotinamide and theophylline reduced the streptozotocin-induced DNA repair. The results suggest that the initial events in streptozotocin-induced B cell injury are DNA damage and repair and that alloxan exerts its major cytotoxic effect by a different mechanism.

Alloxan↗
PubMed1983

Viability tests of cryopreserved endocrine pancreatic cells.

Collagenase-isolated islets, which had been cultured for 1 week, were frozen at two different cooling rates. Islets frozen at 5 degrees C/min behaved from a functional point of view very similarly to that of nonfrozen, cultured control islets, except for a reduced maximal insulin secretory capacity and a reduced insulin content. Slowly frozen islets (0.5 degrees C/min), however, displayed reduced rates of both proinsulin biosynthesis and glucose oxidation. It is concluded that isolated islets can be cryopreserved with great success and that the methods of choice for viability tests are those characterizing the dynamics of insulin secretory capacity of the cryopreserved islets.

Animals↗
PubMed1983

Streptozotocin-induced impairment of islet B-cell metabolism and its prevention by a hydroxyl radical scavenger and inhibitors of poly(ADP-ribose) synthetase.

The possible protective effects in vitro of the hydroxyl radical scavenger dimethyl urea (6 mg/ml) and the poly(ADP-ribose)synthetase inhibitors theophylline (5 mM) and nicotinamide (0.75 mg/ml) against streptozotocin (SZ) induced deterioration of islet metabolism were investigated using isolated mouse pancreatic islets. All these compounds counteracted to different extents the deleterious effects of SZ (4.4 mM) on glucose-stimulated (pro)insulin biosynthesis, dimethyl urea protecting least. No protective effects against SZ were obtained by adding 16.7 mM glucose or 5 mM dibuturyl cAMP. The islet NADH + NAD content decreased drastically when exposed to SZ. Again, nicotinamide and theophylline protected better against the SZ-effects on pyridine nucleotides than dimethyl urea. Furthermore, the maintenance of a linear rate of oxygen uptake was lost after SZ-exposure of the islets, and there was no increase of the respiratory rate when these islets were challenged with high glucose. Also in these islet respiratory studies a partial or total protection by dimethyl urea, theophylline and nicotinamide against SZ was observed. In perifusion experiments SZ rapidly decreased insulin release together with a slightly delayed increased radioactive nucleotide efflux. Later (about 20 min.) a massive leakage of both radioactive nucleotides and insulin occurred in most of the experiments. It is concluded that all the observed impairments of islet metabolism after SZ-exposure can be related to islet NAD depletion, which may depend on poly(ADP-ribose)synthetase activation due to DNA damage. The SZ-induced DNA injury may be mediated by free radicals as suggested by the protective effects of dimethyl urea.

Animals↗
PubMed1983

Effect of interferon therapy on indomethacin-sensitive immunoregulation in the peripheral blood mononuclear cells of renal cell carcinoma patients.

The effect of interferon (IFN) therapy on prostaglandin (PGE)-synthesizing immunoregulatory cell function was assessed in the peripheral blood mononuclear cells of renal cell carcinoma patients. Ten patients were treated daily for 28 days with either 1 X 10(6) IU (five patients) or 10 X 10(6) IU (five patients) of leukocyte IFN. Patient cells were assessed for phytohemagglutinin (PHA) responsiveness in the presence and absence of the PGE synthetase inhibitor indomethacin. Progressive impairment in PHA responsiveness was found in all patients by the end of 28 days of therapy. It was associated with increased levels of indomethacin-sensitive suppressor function. Change in any of the patients studied was not correlated with IFN dose level. There was no correlation between clinical response to IFN and alterations in these parameters of immune function. In co-culture experiments, preincubation of glass-adherent cells with IFN led to increased indomethacin-sensitive regulatory function. These results suggest that IFN can produce progressive impairment of PHA-induced lymphoproliferation by increasing PGE-synthesizing immunoregulatory cell activity.

Adenocarcinoma↗
PubMed1982

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro.

The protective effect on streptozotocin-induced diabetes of dimethyl urea, a hydroxyl radical scavenger, has been evaluated in vivo and in vitro. Pretreatment with dimethyl urea before a single diabetogenic dose of streptozotocin partially protected NMRI mice from hyperglycaemia, whereas the serum glucose of C57BL/KsJ mice increased during week 2 of observation. When the pancreases of these latter mice were examined histologically, insulitis was found in 15 out of 22 animals. The protective effect of dimethyl urea in the NMRI mice was not due to short-term hyperglycaemia induced by the drug, since pretreatment with glucose did not protect from streptozotocin but potentiated its diabetogenic effect. Dimethyl urea reduced the inhibition caused by streptozotocin on proinsulin biosynthesis of NMRI islets in vitro. It is suggested that streptozotocin-induced diabetes in mice may involve generation of hydroxyl radicals which are toxic to islet B cells. If this immediate cytoxicity is reduced by a scavenger, a more slowly developing hyperglycaemia and an accompanying insulitis may occur in particularly susceptible animals.

Animals↗
PubMed1982

Short- and long-term effects of dimethyl sulfoxide on mouse pancreatic islet B-cell function in vitro.

Dimethylsulfoxide has been used as a cryoprotectant for the endocrine pancreas. To explore possible harmful effects of Me2SO influenced neither glucose-stimulated insulin release, nor islet glucose oxidation. On the other hand, 1 M but not 0.25 M Me2SO decreased glucose-stimulated (pro)insulin and total protein biosynthesis in acute experiments. In islet culture experiments with Me2SO-supplemented culture media there was no obvious effects on glucose-stimulated (pro)insulin biosynthesis. It is suggested that Me2SO in the range 0.01-0.5 M does not affect islet B-cell function in vitro.

Animals↗
PubMed1982

Preservation of morphology, insulin biosynthesis, and insulin release in cryopreserved human fetal pancreas.

Human fetal pancreatic glands were obtained from 12 consecutive prostaglandin-induced abortions. Explants cultured for 1 day were frozen at 0.3 degree C/min in a 1 M DMSO-containing medium and stored at -196 degrees C. After storage for 3-4 mo the frozen material was rapidly thawed and cultured 1 day before being tested for functional performance. There was a positive correlation between the pancreatic insulin content and the fetal crown-heel length. Seven of the twelve fetuses showed a marked insulin response to an acute glucose-theophylline challenge. In five of these pancreases there was a well-preserved morphology after thawing, whereas only one of the nonresponding preparations showed a satisfactory morphology. Pancreatic explants from three of four fetuses tested displayed evidences of an (pro)insulin biosynthesis. The combined results indicated that low-temperature storage of human fetal endocrine pancreas is compatible with specific functional survival.

Female↗
PubMed1982

Survival of intrasplenically implanted islets in mice with experimental insulitis and hyperglycemia.

Injections of repeated, subdiabetogenic doses of streptozotocin to C57BL/KsJ mice induced a slowly developing hyperglycemia and pancreatic insulitis similar to that observed in human type I diabetes. It was found that the hyperglycemia could be normalized in these animals by the intrasplenic implantation of syngeneic islets. This could be achieved both 9 and 14 days after the first streptozotocin injection. At the first time point there was a severe insulitis in the pancreas of the recipient. When animals that had been cured by an intrasplenic islet implant were given three subdiabetogenic booster-doses of streptozotocin, they reverted to hyperglycemia. This suggests that cell-mediated immune reactions are of etiologic significance in this diabetes model, since mice made diabetic by a single large dose of streptozotocin and subsequently cured by islet transplantation remained unaffected by the booster-dose administration of streptozotocin. To test the hypothesis that the beta-cell destruction induced by streptozotocin is the triggering mechanism for the insulitis process, syngeneic islets were implanted into the spleen after being exposed in vitro to a weak streptozotocin concentration. This treatment led to normoglycemia in only two of seven alloxan-diabetic recipients. Streptozotocin-treated islets implanted into normoglycemic recipients were recovered intact in the spleens, and pancreatic islet morphology was not influenced by this treatment. The present data do not speak against ongoing attempts to cure human diabetics with islet cell transplantation despite the fact that islet lesions that may reflect immunologic mechanisms are encountered in type I diabetes.

Alloxan↗