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Equilibrative-sensitive nucleoside transporter and its role in gemcitabine sensitivity
D R Rauchwerger1, P S Firby, D W Hedley
1Department of Pharmacology, University of Toronto, Ontario, Canada.
Cancer Research
|November 21, 2000
Summary
Gemcitabine (a pancreatic cancer drug) effectiveness was not directly linked to its cell entry transporter levels. However, inhibiting DNA synthesis with certain drugs before gemcitabine increased transporter levels, potentially improving treatment outcomes.
Area of Science:
- Oncology
- Molecular Pharmacology
- Cancer Therapeutics
Background:
- Nucleoside analogues like gemcitabine are crucial in cancer treatment, with their cellular uptake mediated by nucleoside transporters.
- The equilibrative-sensitive nucleoside transporter (es-NT) facilitates the entry of nucleoside analogues into cells.
- Understanding gemcitabine transport and its relationship with cytotoxicity is vital for optimizing pancreatic cancer therapy.
Purpose of the Study:
- To investigate the correlation between basal equilibrative-sensitive nucleoside transporter (es-NT) levels and gemcitabine cytotoxicity in pancreatic and bladder cancer cell lines.
- To explore the potential of up-regulating the salvage pathway by combining thymidylate synthase (TS) inhibitors with gemcitabine.
- To assess sequence-dependent effects of TS inhibitors and gemcitabine on cancer cell cytotoxicity and es-NT expression.
Main Methods:
- Quantification of basal es-NT levels using flow cytometry in human pancreatic (PANC-1, HS-766T, PK-8) and bladder (MGH-U1) cancer cell lines.
- Assessment of gemcitabine cytotoxicity via clonogenic assays.
- Combination experiments involving TS inhibitors (5-fluorouracil, raltitrexed) and gemcitabine in concurrent and sequential treatment schedules.
Main Results:
- No direct correlation was found between basal es-NT levels and gemcitabine-induced cytotoxicity in the studied cell lines.
- Combination therapy revealed sequence-dependent effects, with TS inhibitors preceding gemcitabine showing maximum cytotoxicity in two pancreatic cell lines.
- TS inhibitors significantly increased es-NT levels, suggesting a mechanism for enhanced gemcitabine uptake.
Conclusions:
- Basal es-NT levels do not predict gemcitabine cytotoxicity in these cancer models.
- Pretreatment with TS inhibitors can up-regulate es-NT expression, offering a potential strategy to enhance gemcitabine's therapeutic efficacy.
- Modulating es-NT activity through TS inhibition may represent a novel approach to improve gemcitabine-based cancer treatment.