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Cellular adaptation to drug exposure: evolution of the drug-resistant phenotype.
Cancer Res. 1997 Nov 15; 57(22):5086-92.CR

Abstract

The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. For etoposide (VP-16), increased expression of MDR-1 or MRP and alterations in topoisomerase IIalpha have been shown to confer tolerance. To further understand resistance to VP-16, three sublines, designated MCF-7-VP17, ZR-75B-VP13, and MDA-MB-231-VP7, were initially isolated as single clones from parental cells by exposure to VP-16. Subsequently, a population of cells from each subline was exposed to 3-fold higher drug concentrations, allowing stable sublines to be established at higher extracellular drug concentrations. Characterization of the resistant sublines demonstrates the adaptation that occurs with advancing drug concentrations during in vitro selections. Reduced topoisomerase II mRNA and protein levels were observed in the initial isolates. This reduction was accompanied by a decrease in topoisomerase II activity and cellular growth rate and was associated with 6-314-fold resistance to topoisomerase II poisons. With advancing resistance, MRP expression increased and VP-16 accumulation decreased. This adaptation allowed for partial restoration of topoisomerase II activity as a result of increased expression (MCF-7-VP17 and ZR-75B-VP13) or hyperphosphorylation (MDA-MB-231-VP7), with a resultant increase in growth rate. In MDA-MB-231-VP7 cells, hyperphosphorylation coincided with increased casein kinase II mRNA and protein levels, suggesting a role for this kinase in the acquired hyperphosphorylation. In this cell line, hyperphosphorylation mediated the increased activity despite a fall in topoisomerase IIalpha protein levels secondary to an acquired 600-bp deletion in one topoisomerase IIalpha allele, which resulted in reduced protein levels. In all three sublines, high levels of resistance were attained as a result of synergism between the reduced topoisomerase IIalpha levels and MRP overexpression. These studies demonstrate how cellular adaptation to increasing drug pressure occurs and how more than one mechanism can contribute to the resistant phenotype when increasing selecting pressure is applied. Reduced expression of topoisomerase II is sufficient to confer substantial resistance early in the selection process, with synergy from MRP overexpression helping to confer high levels of resistance.

Authors+Show Affiliations

Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9371507

Citation

Matsumoto, Y, et al. "Cellular Adaptation to Drug Exposure: Evolution of the Drug-resistant Phenotype." Cancer Research, vol. 57, no. 22, 1997, pp. 5086-92.
Matsumoto Y, Takano H, Fojo T. Cellular adaptation to drug exposure: evolution of the drug-resistant phenotype. Cancer Res. 1997;57(22):5086-92.
Matsumoto, Y., Takano, H., & Fojo, T. (1997). Cellular adaptation to drug exposure: evolution of the drug-resistant phenotype. Cancer Research, 57(22), 5086-92.
Matsumoto Y, Takano H, Fojo T. Cellular Adaptation to Drug Exposure: Evolution of the Drug-resistant Phenotype. Cancer Res. 1997 Nov 15;57(22):5086-92. PubMed PMID: 9371507.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cellular adaptation to drug exposure: evolution of the drug-resistant phenotype. AU - Matsumoto,Y, AU - Takano,H, AU - Fojo,T, PY - 1997/11/26/pubmed PY - 1997/11/26/medline PY - 1997/11/26/entrez SP - 5086 EP - 92 JF - Cancer research JO - Cancer Res VL - 57 IS - 22 N2 - The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. For etoposide (VP-16), increased expression of MDR-1 or MRP and alterations in topoisomerase IIalpha have been shown to confer tolerance. To further understand resistance to VP-16, three sublines, designated MCF-7-VP17, ZR-75B-VP13, and MDA-MB-231-VP7, were initially isolated as single clones from parental cells by exposure to VP-16. Subsequently, a population of cells from each subline was exposed to 3-fold higher drug concentrations, allowing stable sublines to be established at higher extracellular drug concentrations. Characterization of the resistant sublines demonstrates the adaptation that occurs with advancing drug concentrations during in vitro selections. Reduced topoisomerase II mRNA and protein levels were observed in the initial isolates. This reduction was accompanied by a decrease in topoisomerase II activity and cellular growth rate and was associated with 6-314-fold resistance to topoisomerase II poisons. With advancing resistance, MRP expression increased and VP-16 accumulation decreased. This adaptation allowed for partial restoration of topoisomerase II activity as a result of increased expression (MCF-7-VP17 and ZR-75B-VP13) or hyperphosphorylation (MDA-MB-231-VP7), with a resultant increase in growth rate. In MDA-MB-231-VP7 cells, hyperphosphorylation coincided with increased casein kinase II mRNA and protein levels, suggesting a role for this kinase in the acquired hyperphosphorylation. In this cell line, hyperphosphorylation mediated the increased activity despite a fall in topoisomerase IIalpha protein levels secondary to an acquired 600-bp deletion in one topoisomerase IIalpha allele, which resulted in reduced protein levels. In all three sublines, high levels of resistance were attained as a result of synergism between the reduced topoisomerase IIalpha levels and MRP overexpression. These studies demonstrate how cellular adaptation to increasing drug pressure occurs and how more than one mechanism can contribute to the resistant phenotype when increasing selecting pressure is applied. Reduced expression of topoisomerase II is sufficient to confer substantial resistance early in the selection process, with synergy from MRP overexpression helping to confer high levels of resistance. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/9371507/Cellular_adaptation_to_drug_exposure:_evolution_of_the_drug_resistant_phenotype_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9371507 DB - PRIME DP - Unbound Medicine ER -