title: Multiple factors other than p53 influence colon cancer sensitivity to paclitaxel.
abstract: OBJECTIVE
  To determine factors which influence the sensitivity of human colorectal carcinoma cell lines to paclitaxel.
  
  
  METHODS
  The paclitaxel sensitivity of ten human colorectal carcinoma cell lines, and a panel of RKO colon carcinoma cell lines, isogenic except for p53 status, were studied. The inhibitory concentrations causing a 50% decrease in growth (IC50) were assayed after 3, 24, and 96 h after paclitaxel exposure. The doubling time (DT) and cell cycle parameters of cells were also measured. The expression of the multidrug resistance glycoprotein-1 (MDR-1), bcl-2 and bax was quantitatively assessed by immunoblotting.
  
  
  RESULTS
  Mean IC50 values at 24 and 96 h drug exposure were about 1.5 logs lower than the IC50 values at 3 h, regardless of the p53 status. No difference was found between the IC50 values of wild-type and mutant p53 cells, or among the RKO panel of cells. Correlation analysis showed that: (1) resistance was associated with longer DTs, but this was generally abated by a 96-h exposure; (2) with a 3-h exposure, the combination of MDR, bcl-2 and bax parameters with DT (DT + MDR + bcl-2 bax) best correlated with IC50 values (r = 0.77); (3) with a 96-h exposure, in spite of the generally decreased IC50 values, a combination of MDR-1, bcl-2 and bax parameters (MDR + bcl-2-bax) best correlated with the IC50 values (r = 0.71).
  
  
  CONCLUSIONS
  These results suggest that the exposure duration, DT, and expression of MDR-1, bcl-2 and bax each contribute to paclitaxel sensitivity of human colorectal carcinoma cells. In assessing paclitaxel drug resistance, multiple factors should always be considered. There may be a therapeutic window for taxanes in colon cancer by optimizing pharmacokinetics and modulating MDR-1 and bcl-2 resistance factors.
authors.affiliation: Division of Hematology and Oncology, Josephine Ford Cancer Center, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sharma
authors.forename: S
authors.initials: S
authors.lastname: Ramachandran
authors.forename: M
authors.initials: M
authors.lastname: Bowers
authors.forename: M
authors.initials: M
authors.lastname: Yegappan
authors.forename: R
authors.initials: R
authors.lastname: Brown
authors.forename: S
authors.initials: S
authors.lastname: Aziz
authors.forename: R
authors.initials: R
authors.lastname: Chapman
authors.forename: B W
authors.initials: BW
authors.lastname: Yu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005091:Exons / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D017239:Paclitaxel / Q000494:pharmacology*; D018807:Polymorphism, Single-Stranded Conformational; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel