Search PubMed⌕ Search

Biomedical subjects

B L Mirkin

Publications and source records attributed to B L Mirkin.

At least 37 records · Page 2Linked to original sources
PubMed1989

Lack of effect of the opioid antagonist, naltrexone, on the in situ growth of C-1300, N1E-115 and NS206 murine neuroblastoma tumor cell lines.

Attempts have been made to confirm previously reported results which demonstrated that the opioid antagonist, naltrexone, altered the in situ growth of murine neuroblastoma tumors. Adult male A/J mice were injected with tumor cells from three different cell lines of murine neuroblastoma; the spontaneously arising C-1300 line, the adrenergic clonal line N1E-115, and the cholinergic clonal line NS20Y. Naltrexone was administered daily in doses of 0.1, 0.4, or 10.0 mg/kg subcutaneously, to replicate the reported experimental design. In contrast to previous studies, we were unable to demonstrate any effect of naltrexone on in situ growth or other characteristics of tumors produced by the C-1300, N1E-115 or NS20Y murine neuroblastoma cell lines. Ligand binding studies have demonstrated the presence of high levels of opiate binding sites on membranes prepared from the NS20Y clonal cell line and low levels on the membranes of the C1300 tumor line.

Animals↗
PubMed1988

Inhibitory effect of adenosine dialdehyde on in situ murine neuroblastoma growth.

The effect of adenosine dialdehyde (AD) on in situ tumor growth and host survival was evaluated in the C1300 murine neuroblastoma tumor model prepared by implantation of murine neuroblastoma cells into A/J mice. AD was administered s.c. by one of the following treatment regimens: regimen A, single daily dose for 5 days; regimen B, minipump infusion for 7 days; regimen C, minipump infusion for 14 days; regimen D, minipump infusion for two 7-day periods interspersed by a 7-day drug free interval. AD doses of 1.5 to 2.5 mg/kg/day infused over a 7-day period (regimen B) significantly increased the mean life span of tumor bearing mice from 20.9 +/- 1.2 days (mean +/- 2 SEM) in diluent treated controls to 35.3 +/- 2.1 days in AD treated animals (mean increase +/- 2 SEM: 69 +/- 10%; P less than 0.0001). This treatment regimen also produced a 56 +/- 13% decrease in tumor diameter (P less than 0.0001). Administration of AD for two 7-day infusion periods, interspersed by a 7-day drug free interval (regimen D), increased mean life span 80% (controls, 21.3 +/- 4.4 days; AD treated 38.4 +/- 5.6 days; P less than 0.0005). Hematopoietic toxicity was not observed when doses between 2 and 3 mg/kg/day of AD were infused for 7 days (regimen B). These data suggest that steady state infusions of AD can significantly suppress murine neuroblastoma tumor growth with little systemic toxicity. In contrast, single daily injections of AD were ineffective and toxic to the tumor bearing host.

Adenosine↗
PubMed1988

Pyrimidine base degradation in cultured murine C-1300 neuroblastoma cells and in situ tumors.

Dihydropyrimidine dehydrogenase (DPD), the initial, rate-limiting step in pyrimidine degradation, was studied in two cell lines of murine neuroblastoma (MNB-T1 and MNB-T2) that were derived from C-1300 MNB tumor carried in A/J mice. The MNB-T2 (low malignancy) cell line was originally derived from the in situ tumor and carried in tissue culture for more than 100 passages; the MNB-T1 (high malignancy) line consisted of a new sub-culture that was also established from the in situ MNB tumor. DPD activity was determined in cytosolic preparations of MNB utilizing high performance liquid chromatography to separate the radiolabeled substrate ([2-14C]thymine) from [2-14C]dihydrothymine. The apparent affinity of DPD for NADPH in MNB cells (Km approximately 0.08 mM) was identical to that of A/J mouse brain and liver. The DPD activity of the high malignancy (MNB-T1) cell line was 14.3% of that observed in the low malignancy (MNB-T2) line. In situ tumors formed after implantation of high malignancy (MNB-T1) cells into A/J mice had only 25.2% of the DPD activity observed in tumors derived from low malignancy (MNB-T2) cells. When MNB-T2 cells were injected into naive A/J mice, tumors developed in only 68% of animals, the tumor growth rate was slow and a mortality of 20% was observed. In contrast, tumors derived from injected MNB-T1 cells showed a faster growth rate and 100% mortality. Most MNB-T2 derived tumors were not lethal and ultimately resolved while the MNB-T1 derived tumors were invariably lethal. These studies support the concept that the levels of DPD activity in neoplastic cells are inversely related to their malignant expression and also provide a model to study differences between neuroblastoma cell lines derived from the same in situ tumor but which manifest different neoplastic behavior.

Animals↗
PubMed1987

Effects of chemical sympathectomy in neonatal and adult mice on C-1300 neuroblastoma tumor growth and catecholamine content.

The in situ C-1300 murine neuroblastoma (MNB) tumor model was used to investigate the influence of 6-hydroxydopamine (6HD)-induced sympathectomy on tumor growth and catecholamine concentration. One week (adult) and 3 weeks (neonatal) after sympathectomy, mice were implanted with 10(6) disaggregated MNB cells. The time interval between implantation of MNB cells and detection of palpable tumor (tumor onset time), transverse tumor diameter, tumor weight, tumor weight to body weight ratio, and tumor catecholamine concentration were determined. Sympathectomy following 6HD administration was confirmed by analysis of catecholamine concentrations in the heart and spleen by high-pressure liquid chromatography. Treatment of adult animals with 6HD reduced the mean heart and spleen norepinephrine (NE) concentrations to less than 20% of controls (vehicle treated). Neonatal sympathectomy decreased the average heart and spleen NE concentrations to less than 10% of comparable control mice. Whole brain NE and dopamine concentrations were not altered by treatment with 6HD in either age group. Tumor onset time following implantation of MNB cells was significantly increased in animals sympathectomized as either neonates or as adults. In contrast, MNB tumor growth rate following tumor onset was significantly inhibited in animals sympathectomized as neonates but not as adults. The catecholamine concentrations of tumors removed from control and sympathectomized mice 8 days after tumor onset were determined. Tumor NE and dopamine concentrations were increased 9.09 +/- 2.8- (SE) and 7.03 +/- 1.8-fold, respectively, in mice sympathectomized as neonates. There were no significant differences in the NE and dopamine concentrations of tumors obtained from sympathectomized and control adult mice. Pretreatment with desmethylimipramine prior to 6HD administration prevented destruction of sympathetic neurons, inhibition of tumor growth rate, and the increase in tumor catecholamine concentration observed in neonatally sympathectomized mice. These data suggest that the influence of chemical sympathectomy on MNB tumor growth and biochemical differentiation, as defined by catecholamine content, are age dependent.

Age Factors↗
PubMed1987

Effect of adenosine analogues on protein carboxylmethyltransferase, S-adenosylhomocysteine hydrolase, and ribonucleotide reductase activity in murine neuroblastoma cells.

The noncompetitive S-adenosylhomocysteine (AdoHcy) hydrolase antagonist adenosine dialdehyde (AD) has been shown to suppress the growth of cultured C-1300 murine neuroblastoma (MNB) cells. The enzymatic sites at which AD and other nucleoside analogues exert their cytotoxic effects have been postulated to include protein carboxylmethyltransferase (PCM), AdoHcy hydrolase, and ribonucleotide reductase. AD (10(-5) M) increased PCM activity 350% in suspensions prepared from disrupted cells after 72 h of drug exposure; in contrast, 3-deazaadenosine (10(-4) M) increased PCM activity 57%, whereas AdoHcy and sinefungin had no effect. When intact MNB cells were incubated with AD for varying time periods up to 72 h and then pulse labeled with the S-adenosylmethionine precursor L-[3H]-methionine, AD (10(-8) to 5 X 10(-6) M) produced a concentration-dependent inhibition of protein carboxylmethylation which persisted for up to 6 h. Following extended periods of AD treatment (48 to 72 h), AD (10(-6) to 10(-5) M) produced a 250% increment in protein carboxylmethylation, similar in magnitude to that observed in disrupted cell preparations. This increase in carboxylmethylation was observed at timepoints when AdoHcy hydrolase activity remained suppressed. The inhibitory effect of AD on AdoHcy hydrolase activity was maximal within 4 h and still apparent after 72 h of incubation. In contrast, AD treatment had no effect on the ribonucleotide reductase activity of MNB cells. These data suggest that the cytotoxic effect of AD on MNB cells results directly from its inhibition of AdoHcy hydrolase activity and indirectly through its suppression of methyltransferase enzyme systems. The potential linkage between the observed long-term elevations in PCM activity and AD-induced cytotoxicity remains to be defined.

Adenosine↗
PubMed1987

Cytotoxic action of adenosine nucleoside and dialdehyde analogues on murine neuroblastoma in tissue culture: structure-activity relationships.

A series of purine nucleoside and dialdehyde analogues was studied to determine their potency as inhibitors of C-1300 murine neuroblastoma cell growth in tissue culture. Tumor cells were incubated with each analogue for 72 h, and the number of viable cells was determined at 24, 48, and 72 h. Dose-response curves were generated (concentration range, 10(-8) to 10(-3) M), and the drug concentration producing 50% inhibition of cell growth was calculated for each analogue. The 50% inhibitory concentrations, in ascending order of potency, were as follows: adenosine (inactive); S-adenosylhomocysteine (inactive); methylfuryladenine (5.6 X 10(-1)M); adenosine 5'-carboxylic acid (2.0 X 10(-1)M); 5'-chloro, 5'-deoxy-ara-adenosine (3.0 X 10(-2)M); sinefungin (1.7 X 10(-3) M); 5'-deoxyadenosine (2.2 X 10(-4)M); 5'-chloro, 5'-deoxyadenosine (2.1 X 10(-4)M); 3',5'-dichloro, 2',3',5'-trideoxyadenosine (1.3 X 10(-4)M); 3-deazaadenosine (5.6 X 10(-5)M); and adenosine dialdehyde (1.5 X 10(-6)M). Oxidation of the pentose to a dialdehyde increased, whereas reduction of the dialdehyde or substitution of adenine with either hypoxanthine, guanine, uracil, or cytosine decreased the inhibitory potency. The analogues 4',5'-anhydroadenosine dialdehyde and 5'-deoxyadenosine dialdehyde, which cannot be phosphorylated at the 5' position, had 50% inhibitory concentrations of 9.1 X 10(-6) and 7.6 X 10(-6)M, respectively. These data suggest that the inhibitory action and potency of nucleoside dialdehydes on neuroblastoma growth are independent of their capacity to undergo a kinase-mediated phosphorylation at the 5' position.

Adenosine↗
PubMed1987

Elevation of cerebrospinal fluid catecholamine metabolites in patients with intracranial tumors of neuroectodermal origin.

The concentrations of homovanillic acid (HVA), hydroxymethoxyphenylethyleneglycol (HMPG), and vanillylmandelic acid (VMA) were determined in lumbar cerebrospinal fluid (CSF) specimens. The study population consisted of the following groups: control subjects with malignancies of nonneuroectodermal origin (mostly leukemia in remission), neuroblastoma (extracranial and intracranial or cranial metastases), brain tumors (neuroectodermal and glial), and retinoblastoma. A significant increase in the CSF concentration of HVA was observed in patients with brain tumors (neuroectodermal), neuroblastoma (intracranial or cranial metastases), and retinoblastoma when compared with age-matched controls. In contrast, HMPG and VMA concentrations did not differ from controls except in patients with neuroblastoma (intracranial or cranial metastases) and brain tumors (neuroectodermal) who had significant elevations in HMPG and VMA, respectively. An inverse correlation was noted between the CSF concentration of HVA and clinical response to therapy. Nonresponding patients exhibited increases in HVA when compared with pretreatment values. These data suggest that the quantitative determination of catecholamine metabolites in lumbar CSF is an effective method for diagnosing intracranial tumors of neuroectodermal origin and assessing their response to therapy.

Brain Neoplasms↗
PubMed1986

Antihypertensive drug therapy with captopril in children and adolescents.

Captopril was administered to three groups of hypertensive children and adolescents: patients with renal disease; neonates with umbilical artery related hypertension; and post-renal transplant patients. In older children with renal disease, increasing the captopril dose above 0.5 mg/kg did not improve the antihypertensive response. A maximal drug concentrations occurred one hour after dosing, and captopril concentration returned to predose levels by eight hours. Neonates responded to significantly lower doses of captopril (0.01-0.5 mg/kg) and the duration of response to higher doses appeared to be longer than that observed in older children. In post-renal transplant patients, blood pressure decreased after captopril in 94% of subjects, but in 62% a concomitant increase in serum creatinine was observed (correlation [r] = 0.55, p less than .02). This increase could not be correlated with renal biopsy histopathology. Thus, captopril has proven to be an effective antihypertensive agent in children over a broad age range and for a variety of clinical conditions.

Adolescent↗
PubMed1985

Efficacy and safety of captopril in the treatment of severe childhood hypertension: report of the International Collaborative Study Group.

The safety and efficacy of captopril therapy in children with severe and refractory hypertension has been evaluated in a collaborative international study which enrolled a group of 73 patients, 15 years of age or younger. Most patients had hypertension associated with renal disease or vascular abnormalities. Captopril was administered for periods of less than 3 months to more than 1 year. A significant decrease in both systolic and diastolic blood pressures was produced by the administration of captopril, usually in conjunction with other antihypertensive agents (most commonly diuretics and/or beta-blockers). Systolic blood pressures were normalized in 62% and 53% and diastolic blood pressures in 56% and 45% of reported patients after the second and sixth months of captopril therapy, respectively. The response to captopril was sustained over a 12-month period. Adverse reactions were reported in 49% of the 73 patients; 48% of patients had experienced adverse reactions to other antihypertensive agents prior to entering the study. The reactions most frequently observed during captopril therapy were hypotension, vomiting, postural symptoms, anemia, rash, and anorexia. Leukopenia was reported in six patients, all of whom had renal impairment. Two of these patients had received concomitant therapy with immunosuppressants, and one had systemic lupus erythematosus. Captopril was discontinued in two of these six children. Statistically significant increases in mean serum urea nitrogen and potassium concentrations and decreases in mean serum CO2 levels were observed during the course of therapy. These effects could not be exclusively attributed to captopril administration as the study population received multidrug therapy and had significant intrinsic disease. Captopril was demonstrated to be an effective and safe drug for the treatment of children with severe hypertension.

Adolescent↗
PubMed1984

Biological maturation and beta-adrenergic effectors: development of beta-adrenergic receptors in rabbit heart.

The beta-adrenergic receptor, transduction processes and catalytic activity of the adenylate cyclase enzyme complex have been investigated in rabbit heart at different stages of biological maturation. The binding of [3H]-dihydroalprenolol to a washed membrane preparation isolated from rabbit ventricular muscle was used to characterize beta-adrenergic receptors. Significant age-related differences were noted in beta-receptor affinity (Kd) and density (RD) of neonatal and adult animals; the adult Kd was 3.7-fold greater and the RD 2-fold higher than the neonates. No significant differences in these parameters were detected among the 27-day old fetus and the 1- and 7-day old neonates. Age-dependent differences in agonist isoproterenol affinity for the receptor were not observed in contrast to the significant changes in antagonist (DHA) affinity. Age-related changes in receptor affinity were also quantitated by determining the inhibitory potency of alprenolol on isoproterenol stimulated adenylate cyclase enzyme activity. A decreased affinity of the beta-adrenergic receptor for alprenolol in the adult heart was indicated by a 3.7-fold greater Ki for the adult than the 1-day old neonate. Ontogenic variations in the coupling efficiency between the receptor and catalytic components of the adenylate cyclase complex were also evaluated. The Kd of the beta-adrenergic receptor for isoproterenol and the EC50 for adenylate cyclase stimulation were determined under similar conditions. The corresponding coupling index (Kd/EC50) was found to be 2.4-fold greater in the 1-day old neonate than adult, suggesting that for a given percentage increase in adenylate cyclase activity, a lower percentage of beta-adrenergic receptor sites need be occupied in the neonate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1984

Effect of calcium, sodium and isoproterenol on renin secretion from disaggregated rat renal cortical cells.

A disaggregated cell system prepared from rat renal cortices has been developed to study the regulation of renin release in vitro. Cell suspensions were prepared by incubating minced renal cortical tissue in collagenase. The digested tissue was filtered sequentially through graded Teflon meshes of 125 and 44 mu, respectively. This preparation contained less than 2% intact glomeruli or tubules. Incubation of cell suspensions with the beta-adrenergic agonist L-isoproterenol (ISO) significantly increased the activity of renin released into the incubation media. Peak levels of renin activity were detected 10 to 15 min after the addition of ISO. The apparent ED50 for stimulation of renin release by ISO was 6 X 10(-8)M and the response was antagonized by the beta-adrenergic antagonist dl-propranolol. The spontaneous release of renin was also suppressed by increasing the concentration of extracellular calcium, whereas sodium ions had no effect on this process. These data have demonstrated that disaggregated renal cortical cell models are useful for studying the in vitro effects of pharmacologic agents and ions on renin secretion.

Animals↗