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Confluence‐dependent resistance in human colon cancer cells: Role of reduced drug accumulation and low intrinsic chemosensitivity of resting cells
Author(s) -
DimancheBoitrel MarieThéRéSe,
Pelletier Hélène,
Genne Philippe,
Petit JeanMichel,
Grimellec Christian Le,
Canal Pierre,
Ardiet Claude,
Bastian Gérard,
Chauffert Bruno
Publication year - 1992
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910500502
Subject(s) - intracellular , etoposide , doxorubicin , topoisomerase , biology , cell culture , flow cytometry , microbiology and biotechnology , drug resistance , in vitro , cell growth , cancer research , chemotherapy , biochemistry , genetics
In vitro sensitivity of HT29 human colon cancer cells to doxorubicin (DXR), vincristine (VCR), etoposide (VP16), cisplatin (CDDP), melphalan (L‐PAM) and 5‐fluorouracil (5FU) was markedly reduced when cell‐culture density increased. For some drugs, confluence‐dependent resistance (CDR) was partly due to decreased intracellular drug accumulation; the ratio of mean intracellular drug content of non confluent to confluent cells (NC/C) was 2.5 for DXR, 4.1 for VCR and 7.4 for VP16. Altered drug penetration with confluence could be related to decrease of plasma membrane fluidity as measured by the fluorescence polarization method. Reduction of drug intracellular accumulation was nil or weak for L‐PAM (NC/C = 1.0), CDDP (NC/C = 1.2) and 5 FU (NC/C = 1.8). Even if drug concentration was adjusted in culture medium to produce similar intracellular drug content in confluent and non confluent cells, higher intrinsic resistance of confluent cells was still evidenced for DXR and VP16 but not for VCR, the only agent without direct interaction with DNA. DXR‐ and VP16‐induced DNA breakage was also less important in confluent than in non‐confluent cells. CDR appeared closely related to an increased proportion of non‐cycling cells at confluence, as demonstrated by flow cytometry, expression of nuclear antigen recognized by Ki67 MAb and expression of topoisomerase II. CDR is probably a major factor in the poor sensitivity of colorectal adenocarcinomas to chemotherapy.