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[Molecular basis for resistance to anticancer agents and reversal of the resistance]
1Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University, Japan.
Abstract:
The development of drug resistance and especially of multidrug resistance (MDR) is a serious problem during treatment of various malignant tumors. Overexpression of P-glycoprotein (P-gp) has been observed in various multidrug resistant cells. P-gp acts as an energy-dependent drug-efflux pump. We have shown that the expression of P-gp is closely related to clinical drug resistance in some type of leukemia. We have found agents that reverse MDR and elucidated the molecular basis for the reversal of MDR. Thymidine phosphorylase (dThdPase) is an enzyme involved in pyrimidine nucleoside metabolism, but little is known about its physiological functions. We purified dThdPase from human placenta, and isolated partial cDNA clones for dThdPase. Amino-acid sequences were deduced from nucleotide sequences of the longest clone (288 base pairs). This sequence was 100% identical to the sequence of platelet derived endothelial cell growth factor (PD-ECGF) (residues 149-244). dThdPase is one of the activating enzymes for fluorinated pyrimidines. The sensitivity of KB cells transfected with PD-ECGF cDNA to doxifluridine was considerably higher than that of non-transfected KB cells.
Insights
Multidrug resistance (MDR) in cancer is a major challenge. Researchers identified thymidine phosphorylase (dThdPase) as platelet-derived endothelial cell growth factor (PD-ECGF), revealing its role in reversing MDR and enhancing chemotherapy drug sensitivity.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Multidrug resistance (MDR) poses a significant challenge in cancer chemotherapy.
- Overexpression of P-glycoprotein (P-gp) is a key mechanism in MDR, acting as an energy-dependent drug-efflux pump.
- P-gp expression correlates with clinical drug resistance in certain leukemias.
Purpose of the Study:
- To investigate agents that can reverse MDR.
- To elucidate the molecular mechanisms underlying MDR reversal.
- To explore the physiological functions of thymidine phosphorylase (dThdPase).
Main Methods:
- Purification of dThdPase from human placenta.
- Isolation and sequencing of partial cDNA clones for dThdPase.
- Analysis of amino acid sequences and comparison with known proteins.
- Assessment of drug sensitivity in transfected cell lines.
Main Results:
- The deduced amino acid sequence of dThdPase was identical to platelet-derived endothelial cell growth factor (PD-ECGF) (residues 149-244).
- dThdPase functions as an activating enzyme for fluorinated pyrimidines.
- KB cells transfected with PD-ECGF cDNA exhibited significantly higher sensitivity to doxifluridine compared to non-transfected cells.
Conclusions:
- Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF).
- PD-ECGF/dThdPase plays a role in activating fluorinated pyrimidines, potentially reversing MDR.
- This finding offers a novel strategy for overcoming drug resistance in cancer treatment.