Cytotoxic effects and mechanisms of an alteration in the dose and duration of 5-fluorouracil.
5-Fluorouracil (5-FU) is the most routinely administered drug in the treatment of colon cancer. The main mechanism of the drug is not completely understood and its method of administration has been strongly disputed. A 24-hour infusion of 5-FU has clinically yielded better response rates and lower toxicities in comparison to bolus administration, but an exploration into possible mechanisms needs to be performed. Experiments were conducted with two 5-FU resistant cell lines where cytotoxicity, thymidylate synthase (T.S.) activity, thymidine kinase (T.K.) activity, DNA and RNA incorporation, and T.S. expression were contrasted between a 10 microM/24 hour administration of 5-FU (simulating continuous exposure) and a 100 microM/1 hour schedule (simulating bolus administration). After 6 days from the initial exposure, the 10 microM/24 hour schedule (schedule A) inhibited more cell growth than the 100 microM/1 hour regimen (schedule B) by more than 38% and 17% in the two cell lines. After the 6-day observation, schedule A inhibited twice as much T.S. activity as schedule B. Incorporation of [14C]-5-FU into DNA and total RNA was higher in cells exposed to schedule A in comparison to schedule B over the 6 days. T.S. expression and T.K. activity patterns were variable over time. Thus, the exposure of 10 microM/24 hour 5-FU results in superior cytotoxicity when compared to a 100 microM/1 hour regimen and its effectiveness may be explained mechanistically by T.S. activity and DNA and RNA incorporation.
Patel
Manish
M
Department of Hematology and Oncology, Sylvester Comprehensive Cancer Center, University of Miami College of Medicine, 1475 NW 12th Avenue (D8-4) Rm. 3510, Miami, FL 33136, USA.
Ardalan
Katherine
K
Hochman
Ian
I
Tian
Er-Ming
EM
Ardalan
Bach
B
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D012334:RNA, Neoplasm / Q000378:metabolism; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D013940:Thymidylate Synthase; D013937:Thymidine Kinase; D005472:Fluorouracil