2 research outputs found
Evidence for different mechanisms of 'unhooking' for melphalan and cisplatin-induced DNA interstrand cross-links in vitro and in clinical acquired resistant tumour samples
DNA interstrand cross-links (ICLs) are critical lesions produced by several cancer chemotherapy agents including platinum drugs and nitrogen mustards. We have previously shown in haematological (multiple myeloma) and solid tumours (ovarian cancer) that clinical sensitivity to such agents can result from a defect in DNA ICL processing leading to their persistence. Conversely, enhanced repair can result in clinical acquired resistance following chemotherapy. The repair of ICLs is complex but it is assumed that the 'unhooking' step is common to all ICLs
The Molecular Mechanism of Action of Bendamustine
Bendamustine has demonstrated clinical efficacy in the treatment of haematological malignancies and distinguish itself from other alkylating agents. The mechanistic and clinical differences associated with Bendamustine may be related to its structural features including a benzimidazole ring, although the mechanism of action is poorly understood. Understanding the molecular mechanism of Bendamustine could explain the therapeutic efficacy and identify potential biomarkers for response. The Bendamustine-DNA interaction in naked DNA, cytotoxicity, and ICL formation and repair (unhooking) in naked DNA or in cell lines and patient multiple myeloma cells by the single cell gel electrophoresis (comet) assay, were analyzed. DNA damage response (DDR) and potential mechanisms of acquired resistance to Bendamustine were also evaluated. Bendamustine alkylated DNA at guanine-N7 positions, produced ICLs in naked DNA and in cells, and demonstrated a cytotoxic effect comparable to conventional ICL drugs (Cisplatin, Melphalan). However, ICLs were not efficiently repaired (unhooked) in A549 cells, which could repair Cisplatin or Melphalan ICLs. In plasma cells from both Non-Melphalan Treated or Melphalan Treated patients, no evidence of efficient repair of Bendamustine ICLs was observed. Bendamustine DDR compared to Cisplatin or Melphalan gave a more selective pattern of expression of genes involved in DNA damage signaling pathways, cells defective in ERCC1, XPF, and homologous recombination repair showed less sensitivity to Bendamustine, there were differences in Ι£H2AX and RAD51 foci formation and cell cycle distributions. In derived acquired resistant cell lines, resistance was associated with a reduced level of ICL at an equimolar drug dose compared to the parental lines. The molecular mechanism of Bendamustine is similar to conventional alkylating agents: DNA alkylation and ICL formation. However, ICL repair inefficiency and altered DDR are the differences between Bendamustine and conventional alkylating agents due to its benzimidazole ring that influences, showed by G1/S arrest of cell cycle population, its mechanism