Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma
| Autor: | Victoria J. Spanswick, Mallika Sekhar, R. George Hughes, John A. Hartley, Paneesha Shankaranarayana, Prem Mahendra, Charles Craddock, Daniel Hochhauser |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Adult
Male Melphalan DNA Repair medicine.medical_treatment Chronic lymphocytic leukemia Plasma Cells Immunology Biology Biochemistry DNA Adducts Autologous stem-cell transplantation immune system diseases hemic and lymphatic diseases medicine Humans Antineoplastic Agents Alkylating neoplasms Multiple myeloma Aged Chemotherapy Dose-Response Relationship Drug Chlorambucil Cell Biology Hematology Middle Aged medicine.disease Comet assay Kinetics surgical procedures operative Drug Resistance Neoplasm Cancer research Female Comet Assay Stem cell Multiple Myeloma therapeutics DNA Damage medicine.drug |
| Zdroj: | Blood. 100:224-229 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Melphalan is widely used as a preparative agent in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (SCT). Although disease relapse is the major cause of death after a melphalan-conditioned autograft, the mechanism remains unclear. Melphalan produces a number of DNA adducts with the DNA interstrand crosslink (ICL) considered to be the critical cytotoxic lesion. By using a modification of the single-cell gel electrophoresis (Comet) assay, we have measured formation and repair of DNA ICL in plasma cells from melphalan- naive and melphalan-treated patients (ie, those who have relapsed after a melphalan-conditioned autologous SCT or oral melphalan therapy). Similar levels of dose-dependent DNA interstand crosslinking were observed in cells from both melphalan-naive and -treated patients. However, marked differences in ICL repair were observed: cells from naive patients showed no repair, whereas those from treated patients exhibited between 42% and 100% repair at 40 hours. In vitro sensitivity to melphalan in plasma cells was found to correlate with ICL repair. These findings suggest that ICL repair may be an important mechanism by which melphalan resistance emerges after autologous SCT or oral therapy. This mechanism may have implications for MM patients undergoing melphalan therapy. |
| Databáze: | OpenAIRE |
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