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Biomedical subjects

M B Cohen

Publications and source records attributed to M B Cohen.

At least 19 recordsLinked to original sources
PubMed2004

Phase I trial of the novel taxane BMS-184476 administered in combination with carboplatin every 21 days.

The aim of the study was to determine the maximum-tolerated dose and dose-limiting toxicities for BMS-184476, in combination with carboplatin, in patients with advanced solid tumours and to describe any preliminary antitumour activity associated with this regimen. Patients received combination therapy with BMS-184476 given intravenously over 1 h followed by carboplatin administered over 30 min on day 1 of a 21-day cycle. In all, 28 patients received 146 cycles of BMS-184476 and carboplatin. Patients were enrolled at four dose levels: BMS-184476 (mg m(-2))/carboplatin (mg min ml(-1)): 40/5, 50/5, 50/6 and 60/6. Dose-limiting toxicity at 60/6 was neutropenia. Among 27 evaluable patients, 11 demonstrated stable disease for a median of 8.5 cycles. In 22 patients, the pharmacokinetics of BMS-184476 appeared independent of dose of BMS-184476. The mean+/-s.e.m. values for clearance (Cl), volume of distribution at steady state and apparent terminal half-life of BMS-184476 in the four dose groups during cycle 1 were 192+/-25 ml min m(-2), 377+/-69 l m(-2) and 33.7+/-5.9 h, respectively. An increase in the dose of carboplatin from 5 to 6 mg min ml(-1) may have decreased Cl of BMS-184476. BMS-184476 in combination with carboplatin was well tolerated at a dose of 50/6 and shows evidence of antitumour activity in a pretreated population.

Adult↗
PubMed2004

Genetically defined mouse models that mimic natural aspects of human prostate cancer development.

This review is focused on mouse models for prostate cancer that have been designed on the basis of genetic alterations that are frequently found in human prostate cancer. It begins with an analysis of the similarities and differences in the gross and microscopic anatomy of the mouse and human prostate glands, and extends to the pathologies induced in the genetically manipulated mouse prostate in comparison with the sporadic development of the disease in humans. Major achievements have been made in modeling human prostate cancer in mice in recent years. There are models which display slow, temporal development of increasingly severe preneoplastic lesions, which are remarkably restricted to the prostate gland, a property similar to the aging-related progression of these lesions in humans. Other models rapidly progress to local invasive adenocarcinoma, and, in some of them metastasis is manifested subsequently with defined kinetics. Global assessment of molecular changes in the prostate of the genetically manipulated mice is increasingly underscoring the validity of the models through identification of 'signature' genes which are associated with the organ-confined primary or distant metastases of human prostate cancer. Taken together, various 'natural' models depicting stages of the disease, ranging from the early preneoplastic lesions to metastatic prostate cancer, now provide new tools both for exploring the molecular mechanism underlying prostate cancer and for development or testing of new targeted therapies.

Animals↗
PubMed2003

Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumour activity.

Intravesical BCG therapy is effective in the treatment of superficial bladder cancer. Both clinical and experimental results suggest a role for cytokines and delayed-type hypersensitivity (DTH) in BCG-induced antitumour immunity. We characterized the modulatory effects of BCG on bladder cytokine expression and determined the relationship between DTH and BCG antitumour activity. The bladders of mice were instilled with BCG through a catheter. Bladder tissue RNA and urine were collected for evaluation of cytokine expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ELISA. IFN-gamma and TNF-alpha, the two major cytokines associated with DTH, were efficiently induced by BCG. IL10, an important down-regulator of DTH, was also induced by BCG. Constitutive levels of IL4 and IL5 were observed, but neither IL4 nor IL5 were modulated by BCG. Similar results were observed in the kinetic analysis of urinary cytokines in patients after intravesical BCG therapy. Production of Th1 (T helper type 1) cytokines (IFN-gamma, IL2 and IL12) preceded that of the Th2 (T helper type 2) cytokine IL10. A tendency toward higher ratios of IFN-gamma versus IL10 for BCG responders also was observed. In animal studies the absence of IL10 abrogated either by antibody inhibition or the use of genetically modified, IL10 deficient (IL10-/-) mice resulted in enhanced DTH responses. Under conditions of enhanced DTH, a significant enhancement in antitumour activity was observed. These data demonstrate that DTH and its associated mononuclear infiltration and cytokine production are important to the antitumour activity of intravesical BCG therapy, and suggest that effects to diminish IL10 production may have therapeutic value.

Animals↗
PubMed2003

Candidate defense genes from rice, barley, and maize and their association with qualitative and quantitative resistance in rice.

Candidate genes involved in both recognition (resistance gene analogs [RGAs]) and general plant defense (putative defense response [DR]) were used as molecular markers to test for association with resistance in rice to blast, bacterial blight (BB), sheath blight, and brown plant-hopper (BPH). The 118 marker loci were either polymerase chain reaction-based RGA markers or restriction fragment length polymorphism (RFLP) markers that included RGAs or putative DR genes from rice, barley, and maize. The markers were placed on an existing RFLP map generated from a mapping population of 116 doubled haploid (DH) lines derived from a cross between an improved indica rice cultivar, IR64, and a traditional japonica cultivar, Azucena. Most of the RGAs and DR genes detected a single locus with variable copy number and mapped on different chromosomes. Clusters of RGAs were observed, most notably on chromosome 11 where many known blast and BB resistance genes and quantitative trait loci (QTL) for blast, BB, sheath blight, and BPH were located. Major resistance genes and QTL for blast and BB resistance located on different chromosomes were associated with several candidate genes. Six putative QTL for BB were located on chromosomes 2, 3, 5, 7, and 8 and nine QTL for BPH resistance were located to chromosomes 3, 4, 6, 11, and 12. The alleles of QTL for BPH resistance were mostly from IR64 and each explained between 11.3 and 20.6% of the phenotypic variance. The alleles for BB resistance were only from the Azucena parent and each explained at least 8.4% of the variation. Several candidate RGA and DR gene markers were associated with QTL from the pathogens and pest. Several RGAs were mapped to BB QTL. Dihydrofolate reductase thymidylate synthase co-localized with two BPH QTL associated with plant response to feeding and also to blast QTL. Blast QTL also were associated with aldose reductase, oxalate oxidase, JAMyb (a jasmonic acid-induced Myb transcription factor), and peroxidase markers. The frame map provides reference points to select candidate genes for cosegregation analysis using other mapping populations, isogenic lines, and mutants.

Aldehyde Reductase↗
PubMed2003

Mouse strains for prostate tumorigenesis based on genes altered in human prostate cancer.

Animal models of prostate cancer have been limited in number and in relevance to the human disease. With the advancement of transgenic and knockout technologies, combined with tissue specific promoters and tissue-specific gene ablation, a new generation of mouse models has emerged. This review will discuss various animal models and their inherent strengths and weaknesses. A primary emphasis is placed on mouse models that have been designed on the basis of genetic alterations that are frequently found in human prostate cancer. These models display slow, temporal development of increasingly severe histopathologic lesions, which are remarkably restricted to the prostate gland, a property similar to the ageing related progression of this disease in humans. The preneoplastic lesions, akin to what is considered as prostatic intraepithelial neoplasia, are consistent major phenotypes in the models, and, therefore. are discussed for histopathologic criteria that may distinguish their progressions or grades. Finally, considering that prostate cancer is a complex multifocal disease, which is likely to require multiple genetic/epigenetic alterations, many of these models have already been intercrossed to derive mice with compound genetic alterations. It is predicted that these and subsequent compound mutant mice should represent "natural" animal models for investigating the mechanism of development of human prostate diseases, as well as, for preclinical models for testing therapeutics.

Animals↗
PubMed2001

A human volunteer challenge model using frozen bacteria of the new epidemic serotype, V. cholerae O139 in Thai volunteers.

A total of 35 volunteers were recruited for an IRB-approved inpatient dose-escalation challenge. The goal was to identify a dose that produced an observed cholera attack rate > or =80% and an illness of sufficient severity during the defined study period such that the model would be useful for determining vaccine protection. Volunteers were challenged in groups of 5 with V. cholerae O139 that had been reconstituted immediately before use. Only 2 out of 5 volunteers who received the lowest dose (4.3 x 10(4) cfu) had diarrhea. As the inoculum size increased, the attack rate of diarrhea increased to 3-4 of 5 volunteers. At the highest dose tested, approximately 5 x 10(7) cfu, the attack rate was 73%. We recommend the use of frozen V. Cholera O139 in a human experimental challenge model to assess cholera vaccine efficacy (VE) in a cholera endemic area but with 4 days observation period before initiation of tetracycline to allow assessment of severity.

Adult↗
PubMed2001

Bcl-2 oncoprotein protects the human prostatic carcinoma cell line PC3 from TRAIL-mediated apoptosis.

The role of Bcl-2 in TRAIL-induced apoptosis has been investigated in lymphoid cells. Here we show that the human prostatic carcinoma cell line PC3 was sensitive to TRAIL treatment whereas PC3 overexpressing of Bcl-2 was resistant. TRAIL receptors ligation in PC3 activated caspases -2, -3, -7, -8, and -9, induced Bid processing, dissipation of mitochondrial transmembrane potential (Delta Psi(m)), and cytochrome c release. We have detected caspases -8 and -3 only in the cytosolic fraction of cells, but caspases -2, -7, and -9 were found both in cytosolic and mitochondrial fractions. Bcl-2 overexpression did not affect caspase-8 activation although it did change the processing pattern of caspase-3. At the same time, Bcl-2 overexpression inhibited the activation of mitochondrial localized caspases -2, -7, and -9. Bcl-2 also abrogated TRAIL-induced cytochrome c release and dissipation of Delta Psi(m). These findings suggest that TRAIL-induced apoptosis in the epithelial cell line PC3 depends both on mitochondrial integrity and caspase activation.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Increases in guanylin and uroguanylin in a mouse model of osmotic diarrhea are guanylate cyclase C-independent.

BACKGROUND & AIMS: Guanylin and uroguanylin are peptide hormones that are homologous to the diarrhea-causing Escherichia coli enterotoxins. These secretagogues are released from the intestinal epithelia into the intestinal lumen and systemic circulation and bind to the receptor guanylate cyclase C (GC-C). We hypothesized that a hypertonic diet would result in osmotic diarrhea and cause a compensatory down-regulation of guanylin/uroguanylin. METHODS: Gut-to-carcass weights were used to measure fluid accumulation in the intestine. Northern and/or Western analysis was used to determine the levels of guanylin, uroguanylin, and GC-C in mice with osmotic diarrhea. RESULTS: Wild-type mice fed a polyethylene glycol or lactose-based diet developed weight loss, diarrhea, and an increased gut-to-carcass ratio. Unexpectedly, 2 days on either diet resulted in increased guanylin/uroguanylin RNA and prohormone throughout the intestine, elevated uroguanylin RNA, and prohormone levels in the kidney and increased levels of circulating prouroguanylin. GC-C-deficient mice given the lactose diet reacted with higher gut-to-carcass ratios. Although they did not develop diarrhea, GC-C-sufficient and -deficient mice on the lactose diet responded with elevated levels of guanylin and uroguanylin RNA and protein. A polyethylene glycol drinking water solution resulted in diarrhea, higher gut-to-carcass ratios, and induction of guanylin and uroguanylin in both GC-C heterozygous and null animals. CONCLUSIONS: We conclude that this model of osmotic diarrhea results in a GC-C-independent increase in intestinal fluid accumulation, in levels of these peptide ligands in the epithelia of the intestine, and in prouroguanylin in the kidney and blood.

Animals↗
PubMed2001

Reduced expression of dystroglycan in breast and prostate cancer.

Cellular interactions with the extracellular matrix are an important factor in the development and progression of many types of cancer. Dystroglycan is a cell surface receptor for several extracellular matrix proteins and plays a central role in the formation of basement membranes in tissues. Because abnormalities in the structure and function of basement membranes are hallmarks of metastatic disease, we examined the status of dystroglycan expression in prostate and breast tumors. In 15 cases of surgically resected prostate cancer, we noted reduced expression of dystroglycan as judged by intensity of immunohistochemical staining. This reduction was most pronounced in high-grade disease. We found similar results in 6 cases of mammary ductal adenocarcinoma, suggesting that reduced expression of dystroglycan may be a conserved feature of epithelial neoplasia. These data suggest that reduced expression of dystroglycan in prostate and breast cancers may lead to abnormal cell-extracellular matrix interactions and thus contribute to progression to metastatic disease.

Basement Membrane↗
PubMed2001

Biomarkers for the detection of bladder cancer.

In this subject review, a series of morphology-based and molecular markers were compared with urinary cytology for the detection of recurrent urothelial neoplasia. Among the various biomarkers reviewed, the average published sensitivity and specificity for the Bard BTA test was 60% and 77%; the NMP22 Test was 67% and 72%; the telomerase assay was 77% and 85%; and the microsatellite assay was 89% and 100%. DNA ploidy measurements and immunoassays designed to detect keratins, proteins, hyaluronidase, growth factors, cell adhesion molecules, fibrinogen degradation products, cell cycle regulators, and molecular markers were also included. Although the performance features of these biomarkers have varied and the cytologic methods to which they have been compared have not been standardized, several of the procedures have received considerable support from urologists as assisting them in the management of their patients.

Adenocarcinoma↗
PubMed2001

Oral bioavailability and disposition of [14C]omapatrilat in healthy subjects.

The objective of this study was to determine the absolute oral bioavailability and disposition of omapatrilat. This single-dose, randomized, crossover study of 20 mg intravenous and 50 mg oral [14C]omapatrilat was conducted in 12 healthy male subjects to determine the disposition and oral bioavailability of omapatrilat, an orally active vasopeptidase inhibitor. Blood samples were collected up to 120 hours, and the excreta were collected over 168 hours postdose. Plasma concentrations of omapatrilat were determined by a validated LC/MS/MS procedure. Radioactivity in blood, plasma, urine, and feces was determined by liquid scintillation counting. Urinary excretion of radioactivity averaged 80% and 64% of intravenous and oral doses, respectively; < 1% of oral dose was excreted unchanged in urine. The absolute oral bioavailability of omapatrilat averaged 31%. Total body clearance of omapatrilat (80 L/h) exceeded liver plasma flow. Apparent steady-state volume of distribution of omapatrilat (21 L/kg) was extremely high compared with total body water. Omapatrilat undergoes substantial presystemic first-pass metabolism after oral administration. Omapatrilat is eliminated primarily by metabolism, and its metabolites are eliminated primarily in urine. Extrahepatic organs may be involved in the elimination of omapatrilat. Plasma concentrations of omapatrilat exhibit a prolonged terminal elimination phase, which represents elimination from a deep compartment.

Absorption↗
PubMed2001

Detecting recurrent bladder cancer: new methods and biomarkers.

In this review, a series of biomarkers and molecular assays are compared with conventional urothelial cytology in their ability to detect recurrent bladder cancer. The tests considered in detail include the BTA test, NMP 22 test, DNA ploidy measurements, telomerase determinations and microsatellite instability assays. Although all of these measurements show some degree of improvement for cancer detection, the microsatellite instability assay shows the highest sensitivity and specificity. Additional biomarkers considered in the review include bladder cancer tumor antigens, growth factors, cell adhesion molecules and various molecular markers including cell cycle regulatory genes and p53 mutations.

Biomarkers, Tumor↗
PubMed2000

Expression of guanylin is downregulated in mouse and human intestinal adenomas.

Guanylin is a pro-secretory hormone that is expressed in intestinal epithelia. Previously, we mapped the guanylin gene to mouse and human chromosomal regions containing multiple intestinal tumor-modifying loci. Here, we investigate whether guanylin expression is downregulated in precancerous human and mouse intestinal adenomas and whether diminished guanylin expression increases adenoma susceptibility in an animal model of intestinal cancer, the multiple intestinal neoplasia (Min) mouse. In situ hybridization analysis indicated diminished guanylin expression in both mouse and human adenomas. Northern analysis of mouse intestinal tissues showed strain-specific levels of guanylin expression but no correlation with the resistance or susceptibility of each strain to adenoma formation. Similarly, cDNA sequence analysis indicated no inactivating mutations or polymorphisms common to either the high or low adenoma-risk groups. Nonetheless, we have shown that significant loss of guanylin RNA in adenomas of mouse and human is a marker of intestinal epithelial cell transformation.

Adenoma↗
PubMed2000

Cytochrome c is involved in Fas-mediated apoptosis of prostatic carcinoma cell lines.

We have shown previously that the pathways leading to Fas-mediated apoptosis in prostatic carcinoma cell lines are intact, because apoptosis can be triggered either by Fas ligation alone in the Fas-sensitive cell lines PC3 and ALVA31 or by rendering the Fas-resistant cell lines DU145 and JCA1 Fas-sensitive by combined treatment with anti-Fas monoclonal antibody and cycloheximide (O. W. Rokhlin et al., Cancer Res., 57: 1758-1768, 1997). In this study, we demonstrate that two of the early events after Fas ligation are the release of cytochrome c from the mitochondria and activation of caspase-9. We also found that Bid is processed after Fas ligation and thus might activate the mitochondria-dependent apoptotic cascade. In a cell-free system, cytochrome c induced caspase-3-like activity in cytoplasmic extracts from all four cell lines studied, although differences in the level of enzymatic activity were observed. Western blot analysis revealed that caspase-7 is activated by cytochrome c at the same level in all extracts, whereas expression and activation of caspase-3 varied considerably. Cytochrome c-activated extracts displayed different abilities in the induction of apoptotic features in isolated nuclei such as morphological changes and DNA fragmentation. However, differences in nuclear apoptotic activity induced by cytochrome c did not correlate with the level of caspase-3 like activity in the different extracts. These results suggest that the mitochondrial pathway is involved in Fas-mediated apoptosis in prostatic carcinoma cell lines and that, in addition to caspase-7 and caspase-3, there are other factors that confer nuclear apoptotic activity.

Antibodies, Monoclonal↗
PubMed2000

p53 is involved in tumor necrosis factor-alpha-induced apoptosis in the human prostatic carcinoma cell line LNCaP.

The human prostatic carcinoma cell line LNCaP is sensitive to TNF-alpha treatment and expresses wild-type p53. To analyse the possible role of p53 in TNF-alpha-mediated apoptosis, we generated a derivative of LNCaP, LN-56, expressing a dominant-negative element of p53, GSE56. P53 inactivation in LN-56 was associated with an increased resistance to apoptosis induced by TNF-alpha. Surface expression of TNF-alpha receptors was unchanged in LN-56 compared to LNCaP. TNF-alpha treatment resulted in accumulation of p53 in LNCaP and upregulation of p21/WAF1. Activation of caspase-7 and PARP proteolysis were delayed in LN-56 under TNF-alpha treatment. TNF-alpha-induced apoptosis in LNCaP cells was accompanied by caspase-dependent proteolysis of p21/WAF1 and Rb, which was significantly attenuated in LN-56. Cytochrome c release was induced by TNF-alpha treatment in both cell lines, but caspase-9 was not activated. LNCaP and LN-56 were injected s.c. in nude mice and tumors were identified in all LN-56, but not LNCaP, bearing mice indicating that p53 plays an important role in growth control of prostatic neoplasms. Interestingly, accumulation of p53 in TNF-alpha-treated LNCaP cells was decreased in the presence of the caspase inhibitor Z-VAD-FMK, suggesting a new role of activated caspases in acceleration of p53 response. In summary, these results indicate that p53 is involved in TNF-alpha-mediated apoptosis in LNCaP.

Animals↗