Abstract |
Taxol and vinblastine are widely and effectively used in the treatment of cancer, but the initial response to chemotherapy is often hampered by the development of multidrug resistant (MDR) cells. The collateral effects of these two antimitotic drugs on MDA-435 human breast carcinoma cells were investigated. When used at concentrations below those required to depolymerize microtubules, both drugs increased cyclin dependent kinase activity and stimulated the MAPK signal transduction pathway. The activity of MAPK pathway elements and cyclin dependent kinases were found to be constitutively elevated in an MDR cell line that was selected with taxol and expresses high levels of P-glycoprotein. The MDR cells maintained these alterations and also overexpressed hyperphosphorylated RB. This was manifested in a higher growth rate for MDR cells in low serum and an increased ability to form colonies in soft agar. These observations suggest that despite high levels of P-glycoprotein in MDR cells, a sufficient amount of taxol remains intracellular to accelerate the cell cycle machinery and activate the MAPK pathway. These alterations accumulate in resistant cells and contribute to a more transformed phenotype. Thus, in addition to the development of MDR, exposure of tumor cells to antimitotic agents produces further cellular changes that may contribute to the failure of chemotherapy.
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Authors | S L Emanuel, H A Chamberlin, D Cohen |
Journal | International journal of oncology
(Int J Oncol)
Vol. 14
Issue 3
Pg. 487-94
(Mar 1999)
ISSN: 1019-6439 [Print] Greece |
PMID | 10024681
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents
- Antineoplastic Agents, Phytogenic
- Cyclins
- Proto-Oncogene Proteins
- Retroviridae Proteins, Oncogenic
- Vinblastine
- Oncogene Proteins v-raf
- Protein Serine-Threonine Kinases
- Calcium-Calmodulin-Dependent Protein Kinases
- CDC2-CDC28 Kinases
- CDK2 protein, human
- CDK4 protein, human
- Cyclin-Dependent Kinase 2
- Cyclin-Dependent Kinase 4
- Cyclin-Dependent Kinases
- Paclitaxel
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Topics |
- Antineoplastic Agents
(adverse effects, pharmacology)
- Antineoplastic Agents, Phytogenic
(adverse effects, pharmacology)
- CDC2-CDC28 Kinases
- Calcium-Calmodulin-Dependent Protein Kinases
(metabolism)
- Cell Transformation, Neoplastic
(drug effects)
- Cyclin-Dependent Kinase 2
- Cyclin-Dependent Kinase 4
- Cyclin-Dependent Kinases
(biosynthesis, metabolism)
- Cyclins
(metabolism)
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Enzyme Activation
- Humans
- Neoplasms
(chemically induced)
- Oncogene Proteins v-raf
- Paclitaxel
(adverse effects, pharmacology)
- Protein Serine-Threonine Kinases
(biosynthesis, metabolism)
- Proto-Oncogene Proteins
(metabolism)
- Retroviridae Proteins, Oncogenic
(metabolism)
- Signal Transduction
(drug effects)
- Tumor Cells, Cultured
- Vinblastine
(adverse effects, pharmacology)
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