Modulation of the Ribonucleotide Reductase‐Antimetabolite Drug Interaction in Cancer Cell Lines

Abstract

RRM1 is a determinant of gemcitabine efficacy in cancer patients. However, the precision of predicting tumor response based on RRM1 levels is not optimal. We used gene-specific overexpression and RNA interference to assess RRM1's impact on different classes of cytotoxic agents, on drug-drug interactions, and the modulating impact of other molecular and cellular parameters. RRM1 was the dominant determinant of gemcitabine efficacy in various cancer cell lines. RRM1 also impacted the efficacy of other antimetabolite agents. It did not disrupt the interaction of two cytotoxic agents when combined. Cell lines with truncation, deletion, and null status of p53 were resistant to gemcitabine without apparent relationship to RRM1 levels. Pemetrexed and carboplatin sensitivity did not appear to be related to p53 mutation status. The impact of p53 mutations in patients treated with gemcitabine should be studied in prospective clinical trials to develop a model with improved precision of predicting drug efficacy.

Randomized International Phase III Trial of ERCC1 and RRM1 Expression–Based Chemotherapy Versus Gemcitabine/Carboplatin in Advanced Non–Small-Cell Lung Cancer

“…In fact, we have identified and reported at least three parameters that affect these interactions. 24,25 Finally, studies have suggested that the chosen reagent for in situ quantification of ERCC1 (monoclonal antibody 8F1) may detect other molecules of similar immunoreactivity and cellular localization than ERCC1, which may explain the observed lack of correlation in the current study. 26 We have previously reported a modest correlation (r ϭ 0.42) between RRM1 mRNA levels determined in fresh-frozen tumor specimens and in situ protein levels as determined by AQUA from specimens collected at a single institution.…”

Gemcitabine versus Modified Gemcitabine: A Review of Several Promising Chemical Modifications

“…Reduction of RRM1 expression through RNA interference abrogated the induced gemcitabine resistance. 35 Ribonucleotide reductase enzymatic activity is modulated by levels of its M2 subunit. An over-expression of RRM2 is associated with resistance to gemcitabine and down regulation of RRM2 by siRNA enhanced gemcitabine cytotoxicity, both in vitro and in vivo in pancreatic adenocarcinoma.…”

Silencing of ribonucleotide reductase subunit M1 potentiates the antitumor activity of gemcitabine in resistant cancer cells

“…9,35 Therefore, it is possible that the attenuation of RRM1 expression using siRNA technology may also be beneficial to overcoming chemoresistance to those anticancer drugs as well.…”