title: Therapy of malignant brain tumors: comparison of the in vitro activities of vidarabin-monophosphate, BCNU and 5-fluorouracil.
abstract: BCNU (carmustine), 5-Fluorouracil (5-FU) and Vidarabin-monophosphate (ARA-A5'P) were compared in their activities against 30 cell lines of primary (n = 21) and metastatic (n = 9) brain tumors, which were characterized in tissue culture by cytochemical, immunological and cytogenetic criteria. In vivo achievable concentration-time products were correlated with in vitro pharmacokinetic data. A micro assay was employed to screen for drug toxicity in individual tumor cell lines; cells were exposed to the drugs at exposure doses relevant to in vivo pharmacokinetics. After 5-8 population doubling times of untreated controls, RNA-synthesis, as a parameter of cell metabolism and proliferation, was determined by incorporation of (5, 6-3H)-uridine into cellular RNA (liquid scintillation counting protocol). A tumor stem cell assay was performed under similar conditions. The cytotoxic effect of each drug on individual cell lines was expressed in terms of a sensitivity index SI (SI = 1 indicating complete resistance) to compare effects of different drugs on the individual tumor cell lines. Mean sensitivity indices for ARA-A5'P, BCNU and 5-FU in brain tumor cell lines (in brackets: primary CNS-tumors) were 0.64 (0.59), 0.89 (0.82) and 0.35 (0.33) respectively. 5-FU was significantly more active than BCNU and ARA-A5'P (P less than 0.001), whereas BCNU was significantly less active than ARA-A5'P (P less than 0.001). ARA-A5'P had a suppressive effect on formation of brain tumor stem cell colonies. There was no cross-resistance of ARA-A5'P to either BCNU or 5-FU. We conclude that ARA-A5'P and 5-FU are potent agents in experimental therapy of human brain tumors, compared with BCNU.
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002330:Carmustine / Q000378:metabolism / Q000627:therapeutic use*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007700:Kinetics; D014740:Vidarabine / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D014740:Vidarabine; D005472:Fluorouracil; D002330:Carmustine