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Biomedical subjects

L M Rose

Publications and source records attributed to L M Rose.

At least 19 recordsLinked to original sources
PubMed2000

Metabolism of 4'-thio-beta-D-arabinofuranosylcytosine in CEM cells.

Because of the excellent in vivo activity of 4'-thio-beta-D-arabinofuranosylcytosine (T-araC) against a variety of human solid tumors, we have studied its metabolism in CEM cells to determine how the biochemical pharmacology of this compound differs from that of beta-D-arabinofuranosylcytosine (araC). Although there were many quantitative differences in the metabolism of T-araC and araC, the basic mechanism of action of T-araC was similar to that of araC: it was phosphorylated to T-araC-5'-triphosphate (T-araCTP) and inhibited DNA synthesis. The major differences between these two compounds were: (i) T-araC was phosphorylated to active metabolites at 1% the rate of araC; (ii) T-araCTP was 10- to 20-fold more potent as an inhibitor of DNA synthesis than was the 5'-triphosphate of araC (araCTP); (iii) the half-life of T-araCTP was twice that of araCTP; (iv) the catalytic efficiency of T-araC with cytidine deaminase was 10% that of araC; and (v) the 5'-monophosphate of araC was a better substrate for deoxycytidine 5'-monophosphate deaminase than was the 5'-monophosphate of T-araC. Of these differences in the metabolism of these two compounds, we propose that the prolonged retention of T-araCTP is a major factor contributing to the activity of T-araC against solid tumors. The data in this study represent another example of how relatively small structural changes in nucleoside analogs can profoundly affect the biochemical activity.

Animals↗
PubMed2000

Metabolism of O6-propyl and N6-propyl-carbovir in CEM cells.

The metabolism of O6-propyl-carbovir and N6-propyl-carbovir, two selective inhibitors of HIV replication, has been evaluated in CEM cells. Both compounds were phosphorylated in intact cells to carbovir-5'-triphosphate. The metabolism of these two agents was inhibited by deoxycoformycin and mycophenolic acid, but not erythro-9-(2-hydroxy-3-nonyl)adenine. No evidence of the 5'-triphosphate of either compound was detected in CEM cells.

Alkylation↗
PubMed2000

A hypertensive reaction induced by concurrent use of selegiline and dopamine.

OBJECTIVE: To describe a hypertensive reaction induced by concurrent use of selegiline and dopamine. CASE SUMMARY: A 75-year-old critically ill white man who was receiving selegiline 5 mg twice daily for Parkinson's disease was initiated on an intravenous dopamine infusion for decreased urine output and hypotension. Within minutes of starting the dopamine infusion, the patient's systolic blood pressure increased from 105 to 228 mm Hg. Similar reactions occurred during two subsequent rechallenges. DISCUSSION: Since monoamine oxidase is involved in the metabolism of catecholamines, selegiline may have affected the metabolism of the dopamine administered to the patient. Although selegiline is known to be a monoamine oxidase inhibitor specific for type B, evidence exists stating that selegiline may not be as specific as previously thought. CONCLUSIONS: Dopamine should be used cautiously, if at all, in patients who are chronically receiving selegiline or who have received selegiline within the prior two weeks.

Aged↗
PubMed1999

Milestones in the development of Lym-1 therapy.

Lym-1, a monoclonal antibody (MAb) that preferentially targets malignant lymphocytes, has induced therapeutic remissions in patients with advanced non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) when labeled with iodine-131 (131I). Based on the strategy of fractionating the total radiation dose, trials were designed to define the safety, toxicity, and efficacy of a series of doses of 131I-Lym-1 given 2-6 weeks apart. All patients had disease resistant to standard therapy. 131I-Lym-1 was given after unconjugated Lym-1 and the 131I dose was escalated in Phase I-II trials. Therapy proved safe. The dose-limiting toxicity was thrombocytopenia. Nonhematological toxicities did not exceed grade 2 except for infrequent instances of grade 3 hypotension. In a low-dose (LD) trial of 131I-Lym-1, tumor regression occurred in 25 (83%) of 30 patients and 17 (57 %) had durable remissions; 3 of the remissions were complete. In a maximum tolerated dose (MTD) trial of 131I-Lym-1, 10 (71%) of 14 entries that received at least two doses of 131I-Lym-1 therapy and 11 (52%) of 21 total entries had remissions; 7 of the remissions were complete. All 3 entries in the MTD cohort of 100 mCi/m2 [3.7 MBq/m2] of body surface area had durable complete remissions. Therapeutic remission and human anti-mouse antibody (HAMA) after Lym-1 therapy were associated with increased survival that was significant in multivariate analyses. Evidence for an Ab3 idiotypic network with an antibody cytotoxic for Raji human lymphoma was found in the only patient examined in detail thus far; this patient was studied because she had a high titer, HAMA and prolonged survival. In conclusion, 131I-Lym-1 induced durable remissions in patients with chemotherapy-resistant NHL or CLL and was associated with acceptable toxicity. In a subset of the patients, survival was quite prolonged perhaps related to development of Ab3.

Animals↗
PubMed1999

Comparison of the mechanism of cytotoxicity of 2-chloro-9-(2-deoxy-2- fluoro-beta-D-arabinofuranosyl)adenine, 2-chloro-9-(2-deoxy-2-fluoro- beta-D-ribofuranosyl)adenine, and 2-chloro-9-(2-deoxy-2,2-difluoro- beta-D-ribofuranosyl)adenine in CEM cells.

In an effort to understand biochemical features that are important to the selective antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine [Cl-F( upward arrow)-dAdo], we evaluated the biochemical pharmacology of three structurally similar compounds that have quite different antitumor activities. Cl-F( upward arrow)-dAdo was 50-fold more potent as an inhibitor of CEM cell growth than were either 2-chloro-9-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)adenine [Cl-F( downward arrow)-dAdo] or 2-chloro-9-(2-deoxy-2, 2-difluoro-beta-D-ribofuranosyl)adenine [Cl-diF( upward arrow downward arrow)-dAdo]. The compounds were similar as substrates of deoxycytidine kinase. Similar amounts of their respective triphosphates accumulated in CEM cells, and the rate of disappearance of these metabolites was also similar. Cl-F( upward arrow)-dAdo was 10- to 30-fold more potent in its ability to inhibit the incorporation of cytidine into deoxycytidine nucleotides than either Cl-F( downward arrow)-dAdo or Cl-diF( upward arrow downward arrow)-dAdo, respectively, which indicated that ribonucleotide reductase was differentially inhibited by these three compounds. Thus, the differences in the cytotoxicity of these agents toward CEM cells were not related to quantitative differences in the phosphorylation of these agents to active forms but can mostly be accounted for by differences in the inhibition of ribonucleotide reductase activity. Furthermore, the inhibition of RNA and protein synthesis by Cl-F( downward arrow)-dAdo and Cl-diF( upward arrow downward arrow)-dAdo at concentrations similar to those required for the inhibition of DNA synthesis can help explain the poor antitumor selectivity of these two agents because all cells require RNA and protein synthesis.

Adenine Nucleotides↗
PubMed1998

Metabolism and metabolic actions of 6-methylpurine and 2-fluoroadenine in human cells.

Activation of purine nucleoside analogs by Escherichia coli purine nucleoside phosphorylase (PNP) is being evaluated as a suicide gene therapy strategy for the treatment of cancer. Because the mechanisms of action of two toxic purine bases, 6-methylpurine (MeP) and 2-fluoroadenine (F-Ade), that are generated by this approach are poorly understood, mechanistic studies were initiated to learn how these compounds differ from agents that are being used currently. The concentration of F-Ade, MeP, or 5-fluorouracil required to inhibit CEM cell growth by 50% after a 4-hr incubation was 0.15, 9, or 120 microM, respectively. F-Ade and MeP were also toxic to quiescent MRC-5, CEM, and Balb 3T3 cells. Treatment of CEM, MRC-5, or Balb 3T3 cells with either F-Ade or MeP resulted in the inhibition of protein, RNA, and DNA syntheses. CEM cells converted F-Ade and MeP to F-ATP and MeP-ribonucleoside triphosphate (MeP-R-TP), respectively. The half-life for disappearance of HeP-ribonucleoside triphosphate from CEM cells was approximately 48 hr, whereas the half-lives of F-ATP and ATP were approximately 5 hr. Both MeP and F-Ade were incorporated into the RNA and DNA of CEM cells. These studies indicated that the mechanisms of action of F-Ade and MeP were quite different from those of other anticancer agents, and suggested that the generation of these agents in tumor cells by E. coli PNP could result in significant advantages over those generated by either herpes simplex virus thymidine kinase or E. coli cytosine deaminase. These advantages include a novel mechanism of action resulting in toxicity to nonproliferating and proliferating tumor cells and the high potency of these agents during short-term treatment.

3T3 Cells↗
PubMed1998

Polyamine pools in HIV-infected cells.

The polyamines putrescine, spermine, and spermidine, present in all living cells, have been implicated in the replication of some herpesviruses and retroviruses, and elevated levels of these polyamines have been found in the lymphocytes of patients infected with HIV-1. We have examined the effect of HIV-1 infection on polyamine pools in cell culture. HIV-1 did not significantly affect the polyamine pools in CEM cells. Consistent with this observation, inhibitors of the two key enzymes of this pathway, ornithine decarboxylase and S-adenosylmethionine decarboxylase, did not prevent viral-induced cytopathic effects (CPE) in this cell line. Our results indicate that inhibitors of this pathway will not be therapeutically useful in the treatment of AIDS.

Cell Line↗
PubMed1997

Apoptosis in peripheral lymphocytes in systemic lupus erythematosus: a review.

There is increasing evidence to suggest that abnormalities in apoptosis may play a part in the pathogenesis of systemic lupus erythematosus (SLE). For example, there is now considerable evidence that bel-2 expression is enhanced in a proportion of peripheral T cells, but not in B cells, in SLE patients and correlates with overall disease activity regardless of the activity index employed. Further work is required to establish whether enhanced bel-2 expression by some T cells in SLE patients is related to their activation or intrinsically enhanced by genetic predisposition. Mutations in Fas result in a lymphoproliferative syndrome and may play a role in accelerating autoimmune disease. A report of three children with mutations in Fas has once again focused attention on this regulator of apoptosis. The relationships between inducers and inhibitors of apoptosis may differ in different cell types, and must be elucidated before the implications of observations made in lymphocytes from SLE patients can be fully understood.

Animals↗
PubMed1997

Elevated soluble fas production in SLE correlates with HLA status not with disease activity.

Evidence from animal models of lupus suggests that disruption of Fas-mediated apoptotic events may play a role in systemic lupus erythematosus (SLE). The recently described secreted from of Fas (sFas) could interfere with apoptotic events by blockading Fas/Fas ligand interactions. We describe elevated secreted Fas protein in sera from 60 patients with SLE compared with controls but neither sFas protein nor sFas mRNA levels correlated with disease activity. At the mRNA level there is strong evidence that individuals with human leucocyte antigens common in SLE patients have a genetic predisposition for increased secreted Fas production.

Adult↗
PubMed1997

Resolution of CNS lesions following treatment of experimental allergic encephalomyelitis in macaques with monoclonal antibody to the CD18 leukocyte integrin.

Experimental allergic encephalomyelitis (EAE) in macaques is an acute inflammatory and demyelinating disease of the central nervous system (CNS) which has been studied extensively as a model of the human demyelinating disease multiple sclerosis (MS). The in vivo administration of monoclonal antibodies against CD18, the common beta-chain of a leukocyte integrin, at the onset of clinical disease, significantly prolonged the survival of nine of 11 macaques (82%) and in some cases completely reversed the clinical appearance of disease. Treatment with anti-CD18 mAbs dramatically reduced the extent of inflammation in brain lesions as determined by magnetic resonance imaging (MRI). These improvements confirm that anti-CD18 mAbs are powerful anti-inflammatory agents in vivo and suggest that such mAbs may provide effective treatment of both demyelinating and inflammatory CNS diseases in man.

Animals↗
PubMed1996

Lymphoma-selective antibody Lym-1 recognizes a discontinuous epitope on the light chain of HLA-DR10.

The selectivity of Lym-1 for malignant B lymphocytes makes this monoclonal antibody a promising candidate for the delivery of toxic agents to malignant B cells. The original immunogen used for the development of Lym-1 was Raji Burkitt's lymphoma cell nuclei [Epstein A. L., Marder R. J., Winter J. N., Stathopoulos E., Chen F. M., Parker J. W., Taylor C. R. (1987) Cancer Res 47: 830]. The Lym-1 antigen was characterized at that time as a polymorphic HLA-DR variant. We prepared an affinity column using immobilized Lym-1 to isolate the Lym-1 antigen from Raji cell lysate. Immunological characterization of the immunoaffinity-purified Lym-1 antigen on Western blots led to the conclusion that the antigen is the beta chain of HLA-DR10. This was confirmed by Edman sequencing of the isolated polypeptide chain. Western blots further show that the Lym-1 epitope is only recognized if the beta chain disulfide bonds are intact. These results imply that Lym-1 binds a discontinuous epitope on the beta chain of HLA-DR10.

Amino Acid Sequence↗
PubMed1995

Metabolism and metabolic actions of 4'-thiothymidine in L1210 cells.

4'-Thiothymidine (S-dThd) is a potent inhibitor of L1210 cell growth and is active against P388 leukemia in mice. Because of these activities and its novel structure, we have begun studies of its metabolism and metabolic actions in L1210 cells in order to understand its mechanism of cytotoxicity, S-dThd inhibited the incorporation of radiolabeled precursors into DNA, but did not inhibit the incorporation of either uridine or leucine into RNA or protein, respectively, which indicated that the mechanism of its toxicity was due to its inhibition of DNA synthesis. S-dThd did not decrease the concentration of any of the natural deoxynucleoside triphosphates, which indicated that its cytotoxicity was not due to the inhibition of ribonucleotide reductase. S-dThd was readily phosphorylated and used as a substrate for DNA synthesis. Because the rate of incorporation of S-dThd into DNA was 20% that of thymidine, it is likely that the mechanism of action of S-dThd is not due to inhibition of DNA polymerases by the 5'-triphosphate of S-dThd, but instead to its incorporation into the DNA and its subsequent disruption of some function of DNA.

Animals↗
PubMed1995

Experimental allergic encephalomyelitis in non-human primates: MRI and MRS may predict the type of brain damage.

Volume-localized proton spectroscopy and T2-weighted MRI were performed on 23 monkeys with experimental allergic encephalomyelitis (EAE). The purpose of this study was to determine the relationships between temporal changes in lesion activity (measured on T2-weighted MRI), MRS [N-acetyl aspartate (NAA), creatine (CR), choline (CHO)], and the histologic definition of disease determined post-mortem. Animals were scanned in the same areas of the brain once a week before and after sensitization to myelin basic protein (BP). Histologic lesion types were predicted by a combination of preceding MRI and MRS measurements. Acutely fatal EAE lesions were large and monophasic as visualized by MRI, and increased CHO (p < 0.02, n = 16) and CHO/CR ratio (p < 0.001, n = 16) were detected by MRS at disease onset. Chronic EAE lesions were preceded by multiple inflammatory attacks as visualized by MRI and consistently low levels of NAA (p < 0.02, n = 13) and NAA/CR (p < 0.01, n = 13) which occurred after the initial attack. MRI negative brain regions (from animals that were sensitized to BP) were associated with low CHO/CR (p < 0.1, n = 5). The temporal correlation of MRI lesion activity and absolute MRS proton metabolites shows promise for predicting the subsequent duration and histologic type of lesions in EAE in non-human primates.

Animals↗
PubMed1995

Bcl-2 expression is unaltered in unfractionated peripheral blood mononuclear cells in patients with systemic lupus erythematosus.

It has been postulated that the high levels of autoantibodies observed in systemic lupus erythematosus (SLE) patients could result from abnormal longevity of polyclonally activated B-cells. This increased survival could be due to dysfunction of apoptosis, the normal regulatory process governing their life span. The protein product of the bcl-2 gene can enhance lymphoid cell survival by interfering with apoptosis. Moreover, transgenic mice overexpressing bcl-2 in their B-cells developed an autoimmune syndrome resembling SLE. To determine whether overexpression of bcl-2 occurs in SLE patients, bcl-2 protein was measured in peripheral blood mononuclear cells from 73 SLE patients, 20 healthy individuals and 47 patients with other autoimmune diseases. Only three lupus patients had raised levels of bcl-2 and there were no statistically significant differences in the mean bcl-2 levels measured in SLE patients compared to controls. Bcl-2 levels did not correlate with overall disease activity in SLE patients.

Adult↗
PubMed1995

Experimental allergic encephalomyelitis in non-human primates: diffusion imaging of acute and chronic brain lesions.

Diffusion imaging and T2-weighted magnetic resonance imaging were performed on 16 monkeys with experimental allergic encephalomyelitis (EAE), a model of the human demyelinating disease MS. The purpose of this study was to determine whether local changes in diffusion image intensity could be correlated with the formation of acute and chronic demyelinating lesions. Diffusion image analysis was restricted to the internal capsule of the brain because of its anatomic orientation of fiber pathways. Acute inflammatory EAE lesions were large and monophasic, as visualized by T2-weighted MRI, and were accompanied by a decrease in the diffusion MR image signal with the diffusion-sensitizing gradient in all three orthogonal directions (n = 27 brain regions, P < 0.005). Chronic demyelinating lesions were preceded by multiple inflammatory attacks, as visualized by MRI, and by a decrease in diffusion MR image signal with the diffusion-sensitizing gradient in the two orthogonal directions perpendicular to the fibers of the internal capsule (n = 18 brain regions, P < 0.005). However, for the chronic group, there was no significant change in the diffusion MR image signal with diffusion-sensitizing gradient parallel to the fibers of the internal capsule at the terminal scan, suggesting little change in the water diffusion within the nerve fibers. These results suggest that diffusion imaging holds promise for measuring subtle changes in water diffusion due to different types of brain damage.

Acute Disease↗
PubMed1994

Disposition in mice of 7-hydroxystaurosporine, a protein kinase inhibitor with antitumor activity.

UCN-01, a hydroxylated derivative of staurosporine, was selected for study because of its promising antitumor activity. For mice dosed intravenously, subcutaneously, or by oral gavage with this compound, the maximum tolerated doses (MTD) were 20, 10, and > 100 mg/kg, respectively. UCN-01 was stable in mouse and dog plasma, but in human plasma it was converted to a metabolite in a process not inhibited by standard protease and esterase inhibitors. Following an intravenous dose of 10 mg/kg UCN-01, the half-lives for the initial (t1/2 alpha) and terminal (t1/2 beta) exponential phases of elimination were 10 and 85 min, respectively; the area under the plasma concentration-time curve (AUC value) was 117 micrograms min ml-1. In mice dosed by oral gavage with 10 mg/kg, the calculated value for the half-life of the elimination phase was 150 min. The AUC value was 15 micrograms min ml-1, giving a value for bioavailability of 13%. After subcutaneous dosing with 10 mg/kg, the calculated values for half-lives for the distribution and elimination phases were 23 and 130 min, respectively; the AUC value was 113 micrograms min ml-1. Since this value is equivalent to that obtained for intravenous dosing, administration of UCN-01 by the subcutaneous route may be an alternative to intravenous dosing in preclinical and clinical trials.

Administration, Oral↗