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Biomedical subjects

A Rahman

Publications and source records attributed to A Rahman.

At least 181 records · Page 10Linked to original sources
PubMed1996

An improved method of encapsulation of doxorubicin in liposomes: pharmacological, toxicological and therapeutic evaluation.

We describe here an improved method of encapsulating doxorubicin in liposomes using phosphatidylcholine, cholesterol and synthetic tetramyristoyl cardiolipin. With this new composition of lipids the entrapment of doxorubicin was found to be > 90%. Cytotoxicity studies using vincristine-resistant HL-60/VCR leukaemia cells showed that liposome-encapsulated doxorubicin reverses multidrug resistance 5-fold compared with conventional doxorubicin and at levels equivalent to that obtained using liposomes with natural cardiolipin. In normal mice, liposome-encapsulated doxorubicin was much less toxic than the conventional drug. A dose of 25 mg kg-1 i.v. of conventional doxorubicin produced 100% mortality in mice by day 14, whereas liposomal doxorubicin exhibited only 10% mortality by day 60. Liposomal doxorubicin demonstrated enhanced anti-tumour activity against murine ascitic L1210 leukaemia compared with conventional doxorubicin. At a dose of 15 mg kg-1, liposomal doxorubicin increased the median life span with 12 of 18 long-term (60 days) survivors compared with only 3 of 18 with conventional drug. Mice injected i.v. with liposomal doxorubicin had plasma levels 44-fold higher than conventional doxorubicin, producing significantly higher (P < 0.02) area under the plasma concentration curve. An altered tissue distribution was also observed with liposomal doxorubicin; cardiac tissue demonstrating at least 2-fold lower levels with liposomal doxorubicin probably accounting for its lower toxicity. This altered pharmacokinetics of liposome-encapsulated doxorubicin, providing enhanced therapeutic advantage and the ability to modulate multidrug resistance, could be useful in a clinical setting.

Animals↗
PubMed1996

Phage specific for Vibrio cholerae O139 Bengal.

From the stool of a Vibrio cholerae O139 Bengal-infected patient, a phage that specifically lysed capsulated V. cholerae O139 strains only was isolated. The phage is useful for the confirmatory diagnosis of V. cholerae O139 infection and for the differentiation of variants that lack the capsule.

Bacteriophages↗
PubMed1996

TNF alpha mRNA and protein in cardiac transplant biopsies: comparison with serum TNF alpha levels.

OBJECTIVES: To examine the role of TNF alpha (TNF alpha) in cardiac transplant rejection by simultaneous analysis of protein expression and its messenger RNA within serum and grafted tissue. METHODS: 54 endomyocardial biopsy specimens were taken from 19 patients at various times after transplantation. TNF alpha messenger RNA was localised using a digoxygenin labelled complementary DNA probe. An anti-TNF alpha antibody was used to immunohistochemically label the protein product. Serum TNF alpha levels at the time of biopsy were analysed using a specific enzyme-linked immunosorbent assay. RESULTS: TNF alpha mRNA was present in 22/34 endomyocardial biopsies. Eight also contained TNF alpha protein. None had protein alone. Expression did not relate to the grade of rejection in the present or subsequent biopsies. Serum TNF alpha was undetectable (assay sensitivity 30-330 pg/ml) for the majority of specimens. In the nine cases with elevated serum levels, eight samples were from cases within the first 30 days post transplant (r = -0.379; P < 0.05). CONCLUSIONS: Neither tissue TNF alpha mRNA, tissue protein, nor serum TNF alpha relate to the grade of rejection. Furthermore, TNF alpha expression within endomyocardial biopsies is not reflected in the serum. These findings argue against the use of serum analysis as an indicator of cytokine profiles within cardiac tissue allografts. The demonstration of a trend in the early expression of TNF alpha after transplantation suggests that its release may not be specific to the process of rejection.

Adult↗
PubMed1995

A unique thyroid hormone response element in the human immunodeficiency virus type 1 long terminal repeat that overlaps the Sp1 binding sites.

Long terminal repeat (LTR) of human immunodeficiency virus (HIV) type 1 is activated by thyroid hormone (T3) receptor alpha (T3R alpha) in the absence of ligand. Addition of T3 reverses this effect. This activity is mediated by a high affinity T3 response element (T3RE) within the HIV-1 LTR, termed the HIV-T3RE (bases -74 to -50), which coincides with the Sp1 element as demonstrated by mobility shift, DNaseI footprinting, and methylation interference analyses. HIV-T3RE mediates ligand-independent activation of transcription by T3R alpha when linked to a heterologous promoter. In addition, the viral transactivator Tat synergizes with T3R alpha to activate the HIV-1 LTR in the absence of T3, which is relieved in its presence. These findings have implications for the possible control of HIV-1 LTR activity by T3.

Base Sequence↗
PubMed1995

H2O2 and tumor necrosis factor-alpha activate intercellular adhesion molecule 1 (ICAM-1) gene transcription through distinct cis-regulatory elements within the ICAM-1 promoter.

We investigated the mechanisms by which H2O2 increases intercellular adhesion molecule 1 (ICAM-1; CD54) expression in endothelial cells. The H2O2-induced increase in ICAM-1 mRNA was inhibited by actinomycin D, by the antioxidant N-acetylcysteine, and by 3-amino-benzamide (which blocks oxidant-induced AP-1 activity), but not by pyrrolidine dithiocarbamate (which blocks oxidant-induced NF-kappa B activity). Nuclear run-on and transient transfections of ICAM-1 promoter constructs indicated that H2O2 stimulated ICAM-1 gene transcription by activation of a distinct region of the ICAM-1 promoter. The H2O2-responsive element was localized to sequences between -981 and -769 (relative to start codon). Located within this region are two 16-base pair repeats, each containing binding sites for the transcription factors AP-1 and Ets. A similar composite AP-1/Ets element isolated from the macrophage scavenger receptor gene conferred H2O2 responsiveness to a minimal promoter. Mutation of the 16-base pair repeats within the ICAM-1 promoter prevented H2O2-induced DNA binding activity, and their deletion abrogated the H2O2-induced transcriptional activity. In contrast, TNF alpha induced ICAM-1 transcription via activation of promoter sequences between -393 and -176, a region with C/EBP and NF-kappa B binding sites. The results indicate that H2O2 activates ICAM-1 transcription through AP-1/Ets elements within the ICAM-1 promoter, which are distinct from NF-kappa B-mediated ICAM-1 expression induced by TNF alpha.

Animals↗
PubMed1995

Reversal of multidrug resistance in human colon cancer cells expressing the human MDR1 gene by liposomes in combination with monoclonal antibody or verapamil.

BACKGROUND: Colorectal cancer is a major cause of cancer-related mortality in the world and the second leading cause of neoplastic death in the United States. A major obstacle in the chemotherapy of this neoplasm is the emergence of multidrug resistance that is frequently associated with the expression of P-glycoprotein (p170) encoded by MDR1 (also known as PGY1) genes. Previously, we demonstrated that liposome-encapsulated doxorubicin is more cytotoxic than free doxorubicin in human promyelocytic leukemia and human breast cancer cells with the multidrug-resistant phenotype. PURPOSE: Our purpose was to investigate modulation of multidrug resistance by liposome-encapsulated vincristine (VCR) in a drug-resistant human colon cancer cell line HT-29mdr1 and the potentiation of this modulation in combination with monoclonal antibody MRK-16 or verapamil. METHODS: HT-29 parental cells and HT-29mdr1 cells were exposed to free VCR or liposome-encapsulated VCR alone or in combination with MRK-16 or verapamil. Cytotoxicity of cells after various treatments was determined by neutral red staining, and cellular content of VCR was measured by using radiolabeled VCR; p170 expression of cells was assessed by azidopine. RESULTS: HT-29mdr1 cells express a high amount of p170, thus conferring sixfold to sevenfold resistance to VCR compared with the parent cell line. Liposome-encapsulated VCR lowers drug resistance in HT-29mdr1 cells fourfold; IC50 values (concentration that causes 50% reduction in cell number) were 12.5 +/- 2.5 ng/mL compared with 42.5 +/- 5.0 ng/mL with free VCR. IC50 values for free VCR with empty liposomes were 25 +/- 1.25 ng/mL. The combination of MRK-16 and free VCR produced a twofold increase in cytotoxicity over free VCR in p170-expressing cells; the combination of MRK-16 and liposome-encapsulated VCR produced a 10-fold potentiation of cytotoxicity. toxicity. Nonspecific monoclonal antibody NR-LU-10 had no effect on cytotoxicity of HT-29mdr1 cells with free VCR or liposome-encapsulated VCR. The combination of 1.5 microM verapamil potentiated the cytotoxicity of free VCR ninefold to 10-fold, IC50 values reduced to 5.0 +/- 1.5 ng/mL, and in combination with liposome-encapsulated VCR, IC50 values reduced to 2.5 +/- 1.0 ng/mL, demonstrating a 15- to 17-fold potentiation of cytotoxicity. There were no significant differences in drug accumulation in HT-29mdr1 cells when treated with liposome-encapsulated VCR or free VCR. Liposomes inhibited the photoaffinity labeling of azidopine to p170 HT-29mdr1 cells. CONCLUSIONS: Liposome encapsulation of VCR effectively modulates multidrug resistance in human colon cancer cells and may become an important modality in treatment for colon cancers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Characterization of Aeromonas trota strains that cross-react with Vibrio cholerae O139 Bengal.

It has previously been shown that Vibrio cholerae O139 Bengal shares antigens with V. cholerae serogroups O22 and O155. We detected six surface water isolates of Aeromonas trota that agglutinated in polyclonal antisera to V. cholerae O139 and V. cholerae O22 but not in antiserum to V. cholerae O155. On the basis of agglutinin-absorption studies, the antigenic relationship between the cross-reacting bacteria were found to be in an a,b-a,c fashion, where a is the common antigenic epitope and b and c are unique epitopes. The antigen sharing between A. trota strains and V. cholerae O139 was confirmed in immunoblot studies. However, A. trota strains did not react with two monoclonal antibodies specific for V. cholerae O139 and, consequently, tested negative in the Bengal SMART rapid diagnostic test for V. cholerae O139 which uses one of the monoclonal antibodies. A polyclonal antiserum to a cross-reacting A. trota strain cross-protected infant mice against cholera on challenge with virulent V. cholerae O139. All A. trota strains were cytotoxic for HeLa cells, positive for adherence to HEp-2 cells, and weakly invasive for HEp-2 cells; one strain was heat-stable toxin positive in the suckling mouse assay; however, all strains were negative for cholera toxin-like enterotoxin. Studies on bacteria that share somatic antigen with V. cholerae O139 may shed further light on the genesis of V. cholerae O139.

Aeromonas↗
PubMed1995

Detection of provisional serovars of Shigella dysenteriae and designation as S. dysenteriae serotypes 14 and 15.

In initial studies of slide and tube agglutination tests of shigella-like isolates from diarrheal stools from Bangladesh, 10 and 8 strains of Shigella dysenteriae were identified as provisional serovars (serovars that have been defined but not given a number in the antigenic schema) E22383 and E23507, respectively. Further screening of diarrheal stool isolates in a slide agglutination test with antisera (made with the international reference strains) to the two provisional serovars of S. dysenteriae identified an additional 36 isolates as belonging to E22383 and 8 isolates as belonging to E23507. All strains had properties typical of invasive Shigella strains in that they were positive in the Sereny test and had the 120- to 140-MDa plasmid associated with invasiveness. On the basis of these markers of pathogenicity and isolation from various geographical locations, now we recommend that provisional serovars E22383 and E23507 be designated S. dysenteriae serotypes 14 and 15, respectively.

Adolescent↗
PubMed1995

Effect of single-base substitutions in the central domain of virus-associated RNA I on its function.

Adenoviruses use virus-associated RNA I (VAI RNA) to counteract the cellular antiviral response mediated by the interferon-induced, double-stranded-RNA-activated protein kinase PKR. VAI RNA is a highly structured small RNA which consists of two long duplex regions connected at the center by a complex, short stem-loop. This short stem-loop and the adjacent base-paired regions, referred to as the central domain, bind to PKR and inactivate it. Currently it is not known whether binding of VAI RNA to PKR is dependent solely on the secondary (and tertiary) structure of the central domain or whether nucleotide sequences in the central domain are also critical for this interaction. To address this question, 54 VAI mutants with single-base substitution mutations in the central domain of the RNA were constructed, and their capacities to inhibit the autophosphoryation of PKR in vitro were determined. It was found that although about half of the mutants inhibited PKR activity as efficiently as the wild type, a significant number of mutants lost the inhibitory activity substantially, without a perceptible change in their secondary structures. These results indicate that, in addition to secondary structure, at least some nucleotides in the central domain may be critical for the efficient function of VAI RNA.

Adenoviruses, Human↗
PubMed1995

Embryotoxicity of free and liposome-encapsulated taxol in the chick.

Taxol, an inhibitor of microtubule disaggregation, is used in the therapy of breast, ovarian, and other human malignancies. The toxicity of taxol administration is due in part to the polyoxyethylated castor oil (Cremaphor) vehicle in which it is administered; taxol embryotoxicity appears also to be partially attributable to vehicle toxicity. Liposome encapsulation is a novel vehicle for drug administration. The administration of taxol encapsulated in liposomes was evaluated in the chick embryo. Albumen injections of taxol doses up to 30 micrograms/egg were used to characterize dose-response curves for free and liposome-encapsulated taxol, compared to liposome-only and saline-injected control eggs. Sixty percent embryotoxicity (death or malformation) occurred with taxol doses of 1.5 micrograms/egg. A 20-fold higher dose was necessary to produce the same degree of toxicity with liposome-encapsulated taxol. Curve-fitting equations were used to estimate median effective doses (ED50s) and slope functions of the dose response curves. The ED50 for taxol was more than an order of magnitude lower than that for liposome-encapsulated taxol. Estimated slope functions for the two dosage forms of taxol were the same, suggesting similar mechanisms of toxicity. The toxicity of liposomes alone was low.

Abnormalities, Drug-Induced↗
PubMed1994

Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8.

The principal taxol biotransformation reaction of humans and of human hepatic in vitro preparations is 6 alpha-hydroxylation of the taxane ring, but a separate, minor hydroxylation pathway (metabolite B formation) also exists. Taxol metabolism was studied using membrane fractions from Hep G2 cells infected with recombinant vaccinia viruses that contain complementary DNAs encoding several human cytochrome P450 enzymes. Only P450 2C8 formed detectable 6 alpha-hydroxytaxol. Metabolite B formation was catalyzed by complementary DNA-expressed 3A3 and 3A4, but not by 3A5. Each P450 3A preparation catalyzed felodipine oxidation. The apparent Km and Vmax values for taxol 6 alpha-hydroxylation were 5.4 +/- 1.0 microM and 30 +/- 1.5 nmol/min/nmol P450, respectively, for complementary DNA-expressed P450 2C8; the values were 4.0 +/- 1.0 microM and 0.87 +/- 0.06 nmol/min/mg protein, respectively, for human hepatic microsomes. The inhibition of 6 alpha-hydroxytaxol formation by quercetin was competitive with an apparent Ki of 1.3 or 1.1 microM with 2C8 or hepatic microsomes, respectively; retinoic acid was inhibitory, showing an apparent Ki of 27 microM with hepatic microsomes; inhibition by tolbutamide was complex, weak, and unlikely to be clinically relevant. The correlation between hepatic 2C8 protein content and 6 alpha-hydroxytaxol formation was high (r2 = 0.82), while the correlation with 2C9 content was low (r2 = 0.38). These data show that human biotransformation routes of taxol result from catalysis by specific enzymes of two P450 families and that taxol 6 alpha-hydroxylation is a useful indicator of P450 2C8 activity in human hepatic microsomes.

Biotransformation↗