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Codominance of cisplatin resistance in somatic cell hybrids
Yu-Lan Mary Ying1, Ding-Wu Shen, Xing-Jie Liang
1Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4254, USA.
Abstract:
Intrinsic or acquired resistance to cisplatin in cancer cells remains a major obstacle to successful chemotherapy. The clinically relevant genetic and molecular mechanisms of resistance have not yet been identified. Cisplatin-resistant (CP-r) human KB epidermoid carcinoma cell lines (HeLa) resistant to varying levels of cisplatin after single and multiple selection steps are cross-resistant to other platinum compounds and to methotrexate. Intraspecies hybrids of the sensitive and KB CP-r cells were fused with HeLa D98(OR) CP-s, hypoxanthine-aminopterin-thymidine (HAT) sensitive, ouabain resistant, to determine whether cisplatin resistance is dominant or recessive. Cell-cell hybridization between the sensitive cells and single-step or two-step KB CP-r cells both indicated codominance of cisplatin resistance compared to hybrids between sensitive cell lines (D98(OR)xKB). The hybrids between sensitive cell lines (D98xKB) and a single-step CP-r KB cell line (D98xKB-CP.5) also were cross-resistant to carboplatin and methotrexate. In addition, the relatively slower growth rate of CP-r cells appears to be dominant. In the two-step CP-r KB cell line, KB-CP1, resistance is no more dominant than in the single-step CP-r KB cell line, KB-CP.5, suggesting that one of the two steps of resistance in KB-CP1 may not be dominant. These dominance data suggest that it might be possible to identify one or more genes responsible for cisplatin resistance by gene transfer from a resistant cell line to a sensitive cell line.
Insights
Cisplatin resistance in cancer cells shows codominance, suggesting potential for gene identification. This finding advances understanding of chemotherapy resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cisplatin resistance is a significant challenge in cancer chemotherapy.
- The genetic and molecular basis of this resistance is not fully understood.
- Acquired cisplatin resistance in cancer cells can lead to cross-resistance to other platinum compounds and chemotherapeutics.
Purpose of the Study:
- To investigate the inheritance pattern (dominance or recessiveness) of cisplatin resistance in human cancer cell lines.
- To determine if cisplatin resistance is codominant, dominant, or recessive using cell hybridization.
- To explore potential genetic mechanisms underlying cisplatin resistance.
Main Methods:
- Development of cisplatin-resistant (CP-r) human KB epidermoid carcinoma cell lines through single and multiple selection steps.
- Cell-cell hybridization between sensitive and CP-r cell lines (including HeLa D98(OR) CP-s).
- Assessment of resistance levels to cisplatin, carboplatin, and methotrexate in hybrid cell lines.
Main Results:
- Cisplatin resistance demonstrated codominance in hybrids between sensitive and single-step or two-step CP-r KB cells.
- Hybrid cells also exhibited cross-resistance to carboplatin and methotrexate.
- The slower growth rate observed in CP-r cells appeared to be dominant.
- Resistance levels in a two-step resistant cell line (KB-CP1) were not more dominant than in a single-step resistant line (KB-CP.5).
Conclusions:
- The codominance of cisplatin resistance suggests that genes responsible for this trait can be identified.
- Gene transfer studies from resistant to sensitive cell lines may elucidate the molecular mechanisms of cisplatin resistance.
- Understanding these mechanisms could lead to strategies to overcome chemotherapy resistance in cancer patients.