Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines

Abstract

Br" J35of CAnoe (7995$ 71, 914-924 ( )

Tumour markers of prognosis in colorectal cancer

“…Elevated expression of the TS protein has been demonstrated in cell lines which were made resistant to either 5-FU or tomudex (Johnston et al, 1992;Jackman et al, 1995). A higher degree of tumour TS mRNA and protein was observed in patients with a poor response to 5-FU in a small study of colorectal (n = 9) and gastric (n = 12) cancers (Johnston et al, 1995).…”

Resistance to antifolates

“…As observed with DHFR, this is frequently associated with gene amplification. For example, resistance to ZD1694 in human MCF-7 breast cancer, lymphoblastoid, and ovarian carcinoma cell lines, or to ICI-198584 was associated with TS amplification (O'Connor et al, 1992;Freemantle et al, 1995;Jackman et al, 1995;Drake et al, 1996;Tong et al, 1998a;Kitchens et al, 1999a). The relationship between the increase in expression and the level of resistance can vary.…”

Modulation of thymidilate synthase and p53 expression by HDAC inhibitor vorinostat resulted in synergistic antitumor effect in combination with 5FU or Raltitrexed

“…[22][23][24] Preclinical and clinical studies have demonstrated a strong association between increased TS expression and development of resistance to both 5FU and RTX. 20,[25][26][27] Moreover, exposure of cancer cells to 5FU or other TS inhibitors acutely upregulates TS synthesis. The latter effect is likely due to the inhibition of the negative-feedback mechanism in which TS binds its own mRNA and inhibits translation.…”