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Metabolism of 5-fluorouracil in sensitive and resistant tumor cells
Abstract:
Thymidine kinase, dTMP kinase, and DNA polymerase activities were determined in cell lines of AH hepatoma, L1210 leukemia, and Yoshida sarcoma that were sensitive and resistant to 5-fluorouracil (5-FU). It was found that the levels of these enzymes in tumor cells were not consistently related to the property of sensitivity to 5-FU. A marked difference was observed between sensitive and resistant cell lines of L1210 leukemia and Yoshida sarcoma in the uptake of labeled 5-FU into the acid-soluble, nucleotide, and RNA fractions, the rate of incorporation of 5-FU into these fractions being 3 to 5 times greater in sensitive tumor cells than in resistant tumor cells. The radioactivities in the acid-soluble fractions of AH44 (sensitive) and AH109A (resistant) were similar after incubation of these cells with labeled 5-FU in vitro. However, a smaller volume of ascites and lower cell number were observed in AH44 (sensitive)-bearing rats than in AH109A (resistant)-bearing rats. These in vivo results indicate that the 5-FU injected intraperitoneally was diluted by ascites more in AH109A (resistant)-bearing rats than in AH44 (sensitive)-bearing rats.
Insights
Drug resistance to 5-fluorouracil (5-FU) in cancer cells is not solely determined by enzyme levels. Sensitive tumor cells show significantly higher uptake and incorporation of 5-FU compared to resistant cells.
Area of Science:
- Biochemistry
- Cancer Research
- Pharmacology
Background:
- 5-fluorouracil (5-FU) is a widely used chemotherapeutic agent.
- Understanding mechanisms of 5-FU resistance is crucial for improving cancer treatment.
- Enzyme activities and drug uptake are potential factors influencing 5-FU efficacy.
Purpose of the Study:
- To investigate the relationship between enzyme activities (thymidine kinase, dTMP kinase, DNA polymerase) and 5-FU sensitivity in various cancer cell lines.
- To compare the uptake and incorporation of 5-FU in sensitive versus resistant tumor cells.
- To evaluate the in vivo impact of ascites on 5-FU distribution in sensitive and resistant tumor models.
Main Methods:
- Enzyme activity assays in AH hepatoma, L1210 leukemia, and Yoshida sarcoma cell lines.
- In vitro incubation of cell lines with radiolabeled 5-FU to measure uptake into acid-soluble, nucleotide, and RNA fractions.
- In vivo studies comparing ascites volume and cell number in tumor-bearing rats after intraperitoneal 5-FU administration.
Main Results:
- Enzyme levels (thymidine kinase, dTMP kinase, DNA polymerase) did not consistently correlate with 5-FU sensitivity.
- Sensitive L1210 leukemia and Yoshida sarcoma cells exhibited 3-5 times greater uptake and incorporation of labeled 5-FU into cellular fractions compared to resistant cells.
- In vivo, intraperitoneal 5-FU distribution was influenced by ascites volume, with greater dilution in resistant tumor-bearing rats.
Conclusions:
- 5-FU sensitivity is more closely linked to drug uptake and intracellular incorporation than to specific enzyme activities.
- Differential drug distribution due to ascites can impact in vivo 5-FU efficacy.
- Further research into drug transport and metabolism is warranted to fully elucidate 5-FU resistance mechanisms.