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Biomedical subjects

A A Kumar

Publications and source records attributed to A A Kumar.

At least 55 records · Page 3Linked to original sources
PubMed1983

Methotrexate analogues. 20. Replacement of glutamate by longer-chain amino diacids: effects on dihydrofolate reductase inhibition, cytotoxicity, and in vivo antitumor activity.

Chain-extended analogues of methotrexate were synthesized by condensation of 4-amino-4-deoxy-N10-methylpteroic acid with esters of L-alpha-aminoadipic, L-alpha-aminopimelic, and L-alpha-aminosuberic acids, followed by ester hydrolysis with acid or base. Coupling was accomplished in up to 85% yield by the use of the peptide bond forming reagent diethyl phosphorocyanidate at room temperature. The products were found to bind bacterial (Lactobacillus casei) and mammalian (L1210 mouse leukemia) dihydrofolate reductase with an affinity comparable to methotrexate and were also equitoxic to L1210 cells in culture. Cytotoxicity increased up to 3-fold as the number of CH2 groups in the amino acid side chain was extended from two to five. The alpha-aminoadipate and alpha-aminopimelate analogues were poor substrates for carboxypeptidase G1, confirming that this enzyme has a strict requirement for a C-terminal L-glutamic acid residue. The in vivo antitumor activity of the chain-extended analogues against L1210 leukemia in mice was comparable to that of the parent drug on the qd X 9 schedule, but higher doses were required to achieve the same increase in survival. The results were consistent with findings, reported separately, that these compounds are poor substrates for folate polyglutamate synthetase and therefore would not be expected to form gamma-polyglutamates once they enter a cell. This distinctive property has potential therapeutic implications for the treatment of certain MTX-resistant tumors whose resistance may be associated with a lower than normal capacity to form gamma-polyglutamates in comparison with proliferative tissues such as intestinal mucosa or marrow.

Animals↗
PubMed1982

Branch artery occlusion. An unusual complication of external carotid embolization.

A case of retinal branch artery occlusion was caused by migration of emboli, presumably via collateral circulation, during therapeutic embolization of the maxillary artery. Migration of particles to the ophthalmic circulation is unusual with embolization of the branches of the external carotid artery. Meticulous technique, careful angiographic monitoring, and proper selection of embolic material may reduce, but not eliminate, migration of emboli to undesirable locations. Therapeutic embolization of vascular tumors and malformations in the external carotid territory is a recent radiologic innovation that is becoming increasingly popular. Therefore, we may expect to see more ocular complications from aberrant emboli as the use of this technique becomes more widespread.

Adolescent↗
PubMed1982

Lysine and ornithine analogues of methotrexate as inhibitors of dihydrofolate reductase.

The ornithine (6a) and lysine (6b) analogues of methotrexate (1) have been synthesized via condensation of 4-amino-4-deoxy-N10-methylpteroic acid (2) with N gamma-carbobenzoxy-L-ornithine tert-butyl ester (3a) and N epsilon-carbobenzoxy-L-lysine tert-butyl ester (3b), respectively. Removal of the protecting groups gave 5a and 6b. Compounds 6a and 6b and their precursor Cbz acids (5a and 5b) show significant inhibition of dihydrofolate reductase.

Chemical Phenomena↗
PubMed1982

Surgical management of familial benign chronic pemphigus by excision and primary closure.

A case describing primary closure after full-thickness excision of long-standing familial benign chronic pemphigus (Hailey-Hailey disease) in a 54-year-old man is presented. The involved axillary, inguinoscrotal, and perineal skin was excised and closed primarily without difficulty. Eradication of the disease in the excised areas was accomplished with minimal hospitalization and morbidity. Familial benign chronic pemphigus and its differential diagnosis are discussed and the literature on surgical management of this rare disease is reviewed.

Axilla↗
PubMed1981

Affinity labeling of chicken liver dihydrofolate reductase by a substituted 4,6-diaminodihydrotriazine bearing a terminal sulfonyl fluoride.

Chicken liver dihydrofolate reductase is rapidly and stoichiometrically inactivated by a substituted 4,6-diaminodihydrotriazine containing a terminal benzenesulfonylfluoride (DTBSF). The substrate dihydrofolate largely prevents the enzyme inhibition by DTBSF, whereas NADPH had no effect, indicating that the inhibitor is bound at or near the folate site. Using radiolabeled inhibitor between 1.0 and 1.2 mol was incorporated/mol of enzyme (Mr = 21,651), following treatment with 8 M urea at 75 degrees C. Digestion of the maleylated, radiolabeled inhibitor-enzyme complex with trypsin and subsequent gel filtration on Sephadex G-50 SF yielded a single major peak of radioactivity. The covalently modified limited tryptic peptide was subsequently purified to homogeneity using high performance liquid chromatography. The radiolabeled tryptic peptide had the following sequence: Asn-Glu-Tyr (DTBS)-Lys-Tyr-Phe-Gln-Arg (residues 29-36). Automated Edman degradation of this peptide revealed that the radioactivity derived from the inhibitor was released at Step 3, identifying tyrosine-31 as the specific site of covalent attachment of the affinity label.

Affinity Labels↗
PubMed1980

Activation of bovine and chicken liver dihydrofolate reductases and its relationship to a specific cysteine residue in their NH2-terminal amino acid sequences.

The enzymatic activity of bovine liver dihydrofolate reductase is activated approximately 1.5- to 2.5-fold on treatment with organic mercurials. In contrast to the almost instantaneous reaction and high degree of activation (approximately 10-fold) observed with chicken liver dihydrofolate reductase, the beef liver enzyme requires relatively specific conditions of pH, temperature, preincubation times, and presence of substrate to exhibit this degree of activation. It is also demonstrated that both chicken liver and beef liver dihydrofolate reductases (and perhaps all of the animal dihydrofolate reductases) contain a single sulfhydryl group within the 11 or so amino acids of the NH2-terminal sequence and that this is the site of mercurial interaction and activation. On the other hand, this sulfhydryl group and the characteristic activation does not occur in the corresponding bacterial reductases. It is suggested that although the reactive sulfhydryl group may be characteristic of animal dihydrofolate reductases, it is not directly required for substrate binding or the catalytic mechanism per se.

Amino Acid Sequence↗
PubMed1980

Primary structure of chicken liver dihydrofolate reductase.

The complete covalent structure of dihydrofolate reductase from chicken liver is described. The S-carboxymethylated protein was subjected to cleavage by cyanogen bromide which produced five fragments. Fragment CB2 contained an internal homoserine residue which was not cleaved by cyanogen bromide. Sequences and ordering of the cyanogen bromide fragments were established by means of automated sequencer analyses of the fragments and from smaller peptides generated by proteolysis with trypsin and staphylococcal protease. The covalent structure of the single polypeptide chain comprises 189 residues of molecular weight 21,651. The chicken liver enzyme is homologous to that from L1210 cells and shows regions of homology to dihydrofolate reductases from Streptococcus faecium, Escherichia coli, and Lactobacillus casei. These homologous regions in the chicken liver enzyme are primarily related to conserved amino acid residues implicated in the binding of NADPH and methotrexate by bacterial dihydrofolate reductases.

Amino Acid Sequence↗
PubMed1980

Transcatheter embolization in the management of congenital arteriovenous malformations.

Congenital arteriovenous malformations (AVMs) with multiple arterial feeders in eight patients were managed by transcatheter embolization with a combination of polyvinyl alcohol foam (Ivalon), detachable silicone balloons, and wool coils. Due to the extensive number of arterial feeders often present, multiple procedures with several days in between were frequently necessary. When possible, surgical resection after embolization is the procedure of choice. Inoperable AVMs are best managed by segmental distal embolization of all arterial feeders with a permanent occluding material. Embolization therapy as a primary form of management is considered palliative and temporary relief of symptoms is usually achieved.

Adolescent↗
PubMed1975

Liquid nitrogen cryotherapy in the treatment of benign skin lesions.

This article summarizes the use of liquid nitrogen as a cryotherapeutic modality in the treatment of various bening skin lesions. Deep cryosurgery also has been effectively instituted for the treatment of malignant cutaneous lesions, but this article will not describe the latter in detail. Liquid nitrogen is equally as effective as other conventional modalities. Superiority of this treatment is attributed to the simplicity of its application and lack of disfigurement and scarring.

Blood Vessels↗