FR901228, a natural cyclic depsipeptide, shows high cytotoxicity against human cancer cell lines (low nM IC50 values). Cells exposed to FR901228 arrest with G1 or G2/M DNA content; S phase is ...depleted. G2/M cells include cells arrested in mitosis. We wished to understand the mitotic arrest by this compound. Mitotic arrest is often due to interference with microtubules and COMPARE testing in the NCI drug screen indicated a possible taxane-like mechanism. Testing of FR901228 for tubulin binding or alteration of in vitro MT assembly failed to reveal any effect. Likewise, examination of cellular microtubules following exposure to FR901228 did not reveal any change. Similar G2/M accumulation was observed in MCF7, MCF10 and PC3 cells. About 50% of G2/M cells were mitotic and contained microtubule spindles. Mitotic cells peaked at about 14-16 h drug exposure and declined to near 0% by 24-30 h. The block was at prometaphase, with numerous chromosomes unattached to the spindle. We conclude that FR901228 induces formation of aberrant spindles probably by interfering with chromosome attachment, causing mitotic accumulation without affecting mitotic microtubules.
Life-threatening tinnitus Javaheri, Sepehr; Cohen, Victor; Libman, Israel ...
The Lancet (British edition),
07/2000, Letnik:
356, Številka:
9226
Journal Article
Recenzirano
Full blood count, peripheral blood smear, coagulation tests, a biochemistry profile, serum vitamin B12 and folate, thyroid function tests, erythrocyte sedimentation rate, Creactive protein, ...antinuclear antibodies, antineutrophil cytoplasmic antibody, rheumatoid factor, complement levels for C3 and C4, serum protein electrophoresis, cryoglobulins, and quantitative serum immunoglobulins were normal. Cerebrospinal fluid (CSF) analysis showed protein 0.65 g/L and glucose 4.2 mmol/L, 139 red cells and nine white cells per (mu)L (mostly lymphocytes with a few atypical cells). There was no immunological evidence of syphilis (VDRL). CSF cultures and polymerase chain reactions for herpes and cytomegalovirus were negative. Oligoclonal bands were absent. Doppler study of carotid and vertebro-basilar arteries was normal. Gadoliniumenhanced magnetic resonance imaging (MRI) of the head showed bilateral contrast enhancement in the medial aspects of the temporal lobes in the amygdala and hippocampi, as well as in the posterior aspect of the medulla, pons, and midbrain (figure). The imaging was diagnostic for limbic and bulbar encephalitis.1
Previous work investigating the role of MDR-1 overexpression in relapsed and refractory lymphoma led us to investigate a possible role for multidrug resistance-associated protein (MRP) as a cause of ...resistance in patients who did not overexpress MDR-1. A quantitative polymerase chain reaction (PCR) method for measuring MRP expression was validated. Immunoblot analysis suggested that no major discrepancy was present between mRNA expression and protein levels. MRP levels were found to be independent of sample tumor content by immunophenotyping, suggesting that the presence of normal cells had no significant impact on measurements of MRP expression. We evaluated MRP in 55 biopsy samples from 40 patients with refractory lymphoma enrolled on a trial of infusional chemotherapy (EPOCH). Pre- and post-EPOCH samples were available from 15 patients. MRP levels were also evaluated in 16 newly diagnosed, untreated lymphoma patient samples. No significant difference in MRP mRNA expression was noted between pre- and post-EPOCH groups. Also, MRP levels in the newly diagnosed patient samples were not significantly different from either pre- or post-EPOCH groups. Two of 15 paired pre- and post-EPOCH patient samples exhibited overexpression of MRP after EPOCH chemotherapy, with measured increases of 10-fold and 18-fold. We conclude that MRP overexpression is not responsible for non-P-glycoprotein (Pgp)-mediated drug resistance in the majority of these patients, although it may be important in a subset of patients. Defining this subset prospectively could aid in the development of clinical trials of MRP modulation in drug-resistant lymphoma.
The Role of MDR-1 in Refractory Lymphoma Sandor, Victor; Wilson, Wyndham; Fojo, Tito ...
Leukemia & lymphoma,
12/1997, Letnik:
28, Številka:
1-2
Journal Article
Recenzirano
Although lymphoma is one of the few solid tumours for which chemotherapy can be curative, the treatment of refractory lymphoma remains a major clinical problem. P-glycoprotein (Pgp), the drug efflux ...pump encoded by the MDR-1 gene is associated with multidrug resistance in several laboratory models of drug resistance, and a number of investigators have attempted to establish a role for Pgp in refractory lymphoma. Despite a considerable variability in the results of these studies investigating Pgp expression in lymphoma, the preponderance of the data suggests that Pgp may at least in part account for drug resistance in this disease. Several clinical trials using Pgp modulating compounds have attempted to reverse the drug resistant phenotype of refractory lymphoma. These studies, although difficult to interpret because of the effect of Pgp modulators on chemotherapeutic drug pharmacokinetics, also suggest a role for Pgp in mediating drug resistance in a subset of patients with refractory lymphoma. Studies with newer Pgp modulating agents with phase III designs will be needed before Pgp modulation can be considered for incorporation into routine oncologic practice
An assay for the diastereoisomers of the biochemical modifier L-buthionine-(R,S)-sulfoximine (BSO) in human plasma has been developed using capillary electrophoresis (CE). Separation of the ...diastereoisomers is achieved by the micellar electrokinetic chromatography (MEKC) mode of CE. Plasma is injected directly onto the separation capillary without any extraction step, and BSO is detected directly by ultraviolet absorbance measurements at 190 nm without prior derivatization. The whole assay, including capillary conditioning, takes approximately 30 min. Intra- and inter-day R.S.D. values are approximately 7% at sample concentrations around 25 micrograms ml-1, and approximately 3% at sample concentrations around 500 micrograms ml-1. The limit of detection in plasma is 3.9 micrograms ml-1 (S/N = 2). The assay has been used to quantitate the diastereoisomers of BSO in patient samples in a pharmacokinetic study.
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