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Biomedical subjects

A D Kidman

Publications and source records attributed to A D Kidman.

At least 19 recordsLinked to original sources
PubMed1995

Expression of multidrug resistance in response to differentiation in the K562 human leukaemia cell line.

With the increasing use of inducers of cellular differentiation in the treatment of leukaemia, it is essential to understand the relationship between differentiation and the expression of the multidrug resistance. Using the K562 human leukaemia cell line and its multidrug resistant subline K562/E15B, differentiation was examined along two different pathways, megakaryocyte in response to treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA), and erythroid in response to treatment with sodium butyrate, in the same cell line. P-glycoprotein expression was increased in the multidrug resistant K562/E15B subline, but not induced in the parental K562 cell line. However, both treatments conferred a different phenotype on the drug resistant subline. TPA treatment caused an increase in P-glycoprotein, increased drug resistance and decreased rhodamine-123 accumulation which was verapamil sensitive, demonstrating that TPA induced a fully functional P-glycoprotein. However, sodium butyrate treatment caused an increase in P-glycoprotein without increased drug resistance or without decreased rhodamine-123 accumulation suggesting that the P-glycoprotein induced by sodium butyrate was nonfunctional. These results stress the importance of examining not only the expression of P-glycoprotein in cells, but also the function of the P-glycoprotein induced.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Development of drug resistance is reduced with idarubicin relative to other anthracyclines.

Multidrug resistance (MDR) is associated with poor prognosis in leukemia, and anthracyclines, which are used in the treatment of leukemia, are associated with the expression of P-glycoprotein and the development of MDR. We report here that idarubicin, a new anthracycline approved for use in the treatment of acute myelogenous leukemia (AML), did not induce P-glycoprotein expression in the K562 human leukemia cell line under conditions where daunorubicin, doxorubicin and epirubicin did induce expression of P-glycoprotein. The P-glycoprotein expressing, multidrug resistant sublines developed to daunorubicin (K/DNR), doxorubicin (K/DOX) and epirubicin (K/EPR) were cross-resistant to the other anthracyclines and to vinblastine, taxol, colchicine and actinomycin D, but were not resistant to idarubicin or etoposide. The idarubicin treated subline, K/IDA, was only resistant to taxol but was 12-fold sensitized to etoposide, suggesting that idarubicin had affected topoisomerase II in this subline.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Development of extended multidrug resistance in HL60 promyelocytic leukaemia cells.

In an attempt to mimic clinical conditions for the treatment of leukaemia, the HL60 promyelocytic cell line was treated for 18 h with low, clinically relevant, levels of the anthracycline epirubicin and the Vinca alkaloid vinblastine. The resulting drug-resistant sublines not only expressed P-glycoprotein and the MDR phenotype but were also cross-resistant to chlorambucil, methotrexate and cisplatinum, and had increased resistance to radiation. Development of resistance was associated with an aberrant differentiation phenotype with decreased expression of myeloid antigens and expression of glycophorin A, an antigen normally associated with erythroid differentiation. The ability of HL60 cells to terminally differentiate in response to all-trans-retinoic acid (vitamin A acid) was lost in the sublines. These results suggest that either a single novel mechanism is responsible for multiple drug resistance or the initial response to drug treatment is the co-induction of multiple mechanisms. These cells and the method by which they were generated therefore provide a clinically relevant model for the study of the initial events in the development of not only multidrug resistance but also the extended multiple drug resistance usually encountered in the treatment of leukaemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Differentiation and multidrug resistance in response to drug treatment in the K562 human leukaemia cell line.

The relationship between differentiation and P-glycoprotein expression in response to chemotherapeutic drugs was studied in the K562 human leukaemia cell line by treatment with low, but clinically achievable levels of vinblastine and epirubicin. Resistant sublines were easily generated with the multidrug resistant phenotype being expressed in response to drug treatment as low as 1 ng/ml vinblastine and 10 ng/ml epirubicin. These sublines showed stable but heterogeneous expression of P-glycoprotein as revealed by immunocytochemistry, and confirmed by cloning. This heterogeneity was maintained over 18 months with intermittent drug treatment. While selection for resistance induced erythroid and myeloid differentiation, expression of P-glycoprotein was not correlated with the stem cell antigen CD34 or with specific markers of erythroid or myeloid differentiation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

The MTT cell viability assay for cytotoxicity testing in multidrug-resistant human leukemic cells.

The MTT cell viability assay is widely used in determining drug sensitivity profiles for patients with hematological malignancies and in primary screening of potential chemotherapeutic drugs. Because the multidrug resistance (MDR) phenotype is associated with these malignancies, and since many vital dyes are effluxed from MDR expressing cells, we have investigated whether the MDR phenotype interferes with the MTT assay. In CCRF-CEM and K562 human leukemic cell lines and drug-resistant sub-lines developed from them, comparison of the MTT assay with other cell viability assays showed significant variation in IC50 concentrations, although the resistance relative to the sensitive parent cell was correlated. Inclusion of verapamil, an inhibitor of drug efflux activity, had no effect on the MTT assay.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1987

The recovery of slow axonal transport after a single intraperitoneal injection of beta, beta'-iminodipropionitrile in the rat.

A single intraperitoneal injection of beta, beta'-iminodipropionitrile (IDPN) at a dose of 1.5 g/kg was given to 4-week-old rats. Immediately following, or at 1, 2, 3, 5, 10, and 15 weeks after IDPN injection, [35S]methionine was introduced into the anterior horn area of the lumbar cord. Labeled axonal proteins in the sciatic nerve were analyzed electrophoretically and fluorographically at 5, 10, and 15 weeks post-labeling. Labeled neurofilament proteins halt for a short period just after IDPN injection, then continue migrating distally, though at a slower rate, and finally the transport of affected neurofilament proteins completely recovers by 6 weeks post-labeling.

Animals↗
PubMed1986

The long-term effects of a single injection of beta,beta'-iminodipropionitrile on slow axonal transport in the rat.

Following a single intraperitoneal injection of beta,beta'-iminodipropionitrile (IDPN) simultaneously with or 5 weeks after injection of [35S]methionine into the ventral horn area of rat spinal cord, the changes of slowly migrating axonal proteins were analyzed electrophoretically up to 10 weeks after labeling, and the following results were obtained. After a single injection of IDPN, only the transport of neurofilament proteins is inhibited, leaving that of tubulin and actin almost unaffected, though a small portion of the former was retarded through the interaction with neurofilaments. The inhibitory effect of IDPN on neurofilament transport is not a complete blockage, but a slowing of the rate of transport to about a half of the control with a possible short halting period just after IDPN treatment. The dose-response data indicate a threshold between 0.5 and 1.0 g/kg of body weight, increasing the dose above which does not further affect the neurofilament transport. The transport of neurofilaments is uniformly impaired by IDPN along the whole axon.

Animals↗
PubMed1984

Quantitation of the Schmidt-Lanterman incisures in juvenile, adult, remyelinated and regenerated fibres of the chicken sciatic nerve.

Morphometric studies of peripheral nerves in various species have shown that the number of Schmidt-Lanterman incisures in an internode is proportional to the fibre diameter. In the rat sural nerve it appears that following remyelination, the relationship between the numbers of incisures per internode and the fibre diameter remains unaltered despite the fact that the remyelinated internodes are uniformly short. We quantitatively examined the insertion of incisures in adult, juvenile, remyelinated and regenerated fibres of the chicken sciatic nerve. Remyelinated fibres were examined 100 and 200 days following the intraneural injection of diphtheria toxin, and regenerated fibres 200 days after a nerve crush. Our results show that the incisures are more abundant in the chicken than in all other species previously reported, and for both juvenile and adult hens the number of incisures in an internode is proportional to the fibre diameter. Following both remyelination and regeneration the internodal lengths were shorter than control fibres and the distances between the incisures were reduced by approximately 20% for all fibre diameters. Significantly, the numbers of incisures in an internode were related to the length of the remyelinated or regenerated internode and not to the fibre diameter. This finding is in marked contrast to previous reports for rat peripheral nerve. Our findings are discussed in relation to the hypothesis that the Schmidt-Lanterman incisures are vital to the maintenance of the myelin sheath and/or the associated axon.

Age Factors↗
PubMed1982

In vitro skeletal muscle protein and RNA incorporation in neuromuscular disease.

Skeletal muscle of Duchenne muscular dystrophy (DMD) patients, DMD carriers and of patients with other neuromuscular diseases was sampled at diagnostic muscle biopsy. The incorporation of isotopic precursors into protein and RNA in a 1-hour in vitro incubation of these samples was then determined. Individual DMD results overlap with these obtained with normal muscle, and an inverse relationship is observed between DMD patient age and incorporation into skeletal muscle protein. The protein and RNA incorporation of DMD carrier skeletal muscle was normal. Limb-girdle dystrophy shows an increase in protein incorporation, while nemaline myopathy, dystrophia myotonica and polymyositis show increases in both protein and RNA incorporation over normal skeletal muscle. The significance of the incorporation observed in the neuromuscular disorders studied in discussed.

Adolescent↗
PubMed1980

Monoamine and tissue fluid levels in contused spinal cord of sheep.

Methods are described for the determination of sheep spinal cord tissue fluid content and norepinephrine, serotonin, and dopamine concentrations after experimental injury. The amount of tissue fluid varied in different regions of sheep spinal cord following injury. Norepinephrine and serotonin wet weight concentrations were corrected for this variation in tissue fluid. Corrected norepinephrine wet weight cord concentrations did not change up to 3 hr after injury. Levels of serotonin at 60 min after injury were similar to controls. Dopamine was not detected in sheep spinal cord. alpha-Methyl tyrosine significantly reduced fluid in the spinal cord at 75 min after injury.

Animals↗
PubMed1979

In vitro radioisotope precursor incorporation into ribonucleic acid and protein in dystrophic mouse gastrocnemius muscle (C57 BL/6J dy2J/dy2J).

An in vitro tissue slice technique has been developed and used to compare radioisotope precurosr incorporation into RNA and protein in normal and dystrophic mouse gastrophic muscle. Significant differences are observed with both RNA and protein when incorporation is measured on a fresh weight of muscle basis. Specific activity comparisons show significantly increased incorporation with protein but not with RNA. A comparison of the results with in vivo studies has been made. The in vitro system developed is applicable to the study of macromolecular metabolism in normal and diseased human muscle tissue.

Animals↗
PubMed1978

Effect of diphtheritic demyelination on axonal transport in the sciatic nerve and subsequent muscle changes in the chicken.

Chicken sciatic nerves undergo demyelination following intraneural injection of diphtheria toxin and subsequent atrophy of some muscular cells. Paresis occurs after one week and lasts approximately three weeks; at the height of the lesion C14-leucine was injected into the ventral horn cells of the spinal cord. The axonal transport of fast flowing labelled proteins was followed down the sciatic nerve axons and flow rates at two different times were measured. Muscle cells were stained for succinic dehydrogenase and ATPase; fibre diameters, total protein, and total radioactivity associated with the nerves were also measured. The results showed that the fast flowing labelled proteins accumulated at the demyelination site while the muscle cells supplied by these nerves showed reduction of fibre diameter and evidence of degeneration. Further studies are in progress on slow moving proteins and muscle cells.

Animals↗
PubMed1975

The experimental contusion injury of the spinal cord in sheep.

The validity of reproduction of the controlled contusion injury to the spinal cord in the experimental animal is questioned. The dynamic pathology involving the microvasculature within the first two hours is illustrated using light microscopy. After 15-30 minutes swelling of axons and disruption of myelin sheaths become evident in most areas of white matter. After four hours microcysts have formed in the columns of white matter and are evidence of irreversible damage. Swelling of the cord following injury results from congestion, extravasation and intracellular swelling of neurones, rather than from any demonstrable increase in extracellular fluid. Oedema was only demonstrated with perfusion fixation. Isotope and contrast myelography were compared in the identification of the degree and extent of spinal cord swelling. Significant improvement in motor power was found in a group of paraplegic sheep treated with alpha-methyl paratyrosine. There was no significant improvement in the degree of recovery of motor power or sensation in those animals treated with intrathecal methyl prednisolone (Depo-Medrol). The histopathology in the crushed spinal cord tissue of the treated and untreated animals at various intervals of time was compared. Some possible explanations for the different patterns of clinical recovery in the treated animals are discussed.

Animals↗