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Biomedical subjects

P Borst

Publications and source records attributed to P Borst.

364 records · Page 21Linked to original sources
PubMedDate not supplied

Multidrug resistance and the role of P-glycoprotein knockout mice.

Drug resistance, be it intrinsic or acquired, is a major problem in cancer chemotherapy. In vitro, one well characterised form of resistance against many different cytotoxic drugs is caused by the MDR1 P-glycoprotein, a large plasma membrane protein that protects the cell by actively pumping substrate drugs out. Available evidence suggests that this protein may cause drug resistance in at least some clinical tumours. Drugs inhibiting the MDR1 P-glycoprotein activity are, therefore, co-administered during chemotherapy of these tumours. To predict the biological and pharmacological effects of the blocking of this protein, we have generated mice with a genetic disruption of the drug-transporting mdr1a P-glycoprotein. These mice are overall healthy, but they accumulate much higher levels of substrate drugs in the brain, and have markedly slower elimination of these drugs from the circulation. For some drugs, this leads to dramatically increased toxicity, indicating that P-glycoprotein inhibitors should be used with caution in patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Growth of chromosome ends in multiplying trypanosomes.

Some of the genes for the variant surface glycoproteins of trypanosomes are located close to a discontinuity in the DNA, presumably a chromosome end. We show here that DNA fragments containing these telomeres increase in length in multiplying trypanosomes at a rate of about 10 base pairs per division. We argue that chromosome growth may not be restricted to trypanosomes and could explain the heterogeneity of telomeric DNA fragments observed in some other organisms.

Animals↗
PubMedDate not supplied

Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome).

The Zellweger syndrome is a lethal hereditary disease characterized by the absence of peroxisomes (microbodies) in liver and kidney, and variable abnormalities in mitochondria. We show here that tissues from five infants that had died of this syndrome contain less than 10% of the normal levels of phosphatidylethanolamine plasmalogen (pPE), a major phospholipid component of cellular membranes. Heart and muscle, but not other tissues, also contain a substantial fraction of phosphatidylcholine plasmalogen (pPC), and this fraction is also strongly reduced in the Zellweger patients. No other abnormalities in cellular phospholipids were detected. Key enzymes of the biosynthesis of plasmalogens have previously been shown to be exclusively located in the peroxisomes of rodent liver and the microperoxisomes of rodent brain. We infer that the corresponding enzymes are also located in peroxisomes in man and that the absence of peroxisomes in Zellweger patients leads to their inability to synthesize plasmalogens. Our results support the notion that the biosynthetic role of peroxisomes in mammals has thus far been underestimated. We suggest that the defect in plasmalogen synthesis and possibly as yet unknown peroxisomal reactions are responsible for the diverse abnormalities observed in Zellweger patients.

Abnormalities, Multiple↗