We have characterized the cell population dynamics of survival/death that underlie the acquisition of drug resistance in the HT-29 colon cancer cell model (Lesuffleur et al., Cancer Res 1990, 50:6334-43) and proposed a new mechanism – dynamic selection – for the emergence of tumor cell variants resistant to methotrexate (de Anta et al., Biochim Biophys Acta 2005,1721:98-106; de Anta et al., Int J Cancer 2006, 119:1607-15). We have also found that the cell cycle checkpoint machinery, especially the pathway induced in response to DNA damage, is a major determinant of cell survival/resistance to methotrexate treatment (de Anta et al., Anticancer Drugs 2006, 17:1171-7); hence, our results, together with work of others in this field, supports the notion that cell cycle checkpoints are putative targets to improve the efficacy of anticancer drugs.
Dynamic selection of methotrexate resistance in HT-29 colon cancer cells. Continous treatment of cells surviving to a 10-day course treatment (A) leads to the selection of permanently-resistant cell clones after 60 days (B, large colonies), which are defined as those displaying increased growth ability after isolation in control medium and re-treatment (C). Large colonies shown in B were picked up, grown without the drug, and treated again for 5 days with 10-7 M MTX (colonies 1 to 15 in C) in parallel with the paretal HT-29 population (HT-29) and populations resistant to 10-6 M (HT-29 M6) or 10-7 M MTX (HT-29 M7-1, HT-29 M7-2); data shown is the percentage of cells respect to non-treated cultures after the 5-day treatment experiment.
Contact: Xavier Mayol, xmayol(ELIMINAR)@imim.es, tel 93.316.04.24, fax 93.316.04.10.