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Abstract
Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and cisplatin are commonly
used in the treatment of many solid tumors, although the impact of chemotherapy is
limited in metastatic non-small cell lung cancer. However, in clinical practice, there
is a minority of patients who can attain long-term survival. Upregulation of mRNA
transcripts has been linked to chemoresistance, and in some instances, mRNA expression
has been correlated with polymorphisms. Cisplatin resistance is directly linked to
the nucleotide excision repair system, specifically to the transcription-coupled nucleotide
excision repair pathway that involves genes that are deficient in rare inborn disorders
such as Cockayne syndrome and xeroderma pigmentosum. Overexpression of ERCC1 correlates
with poor survival in gemcitabine/cisplatin-treated non-small cell lung cancer patients.
At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other,
and overexpression of XPD causes selective cisplatin resistance in human tumor cell
lines. XPD polymorphisms have been associated with lower DNA repair capacity. In our
experience, time to progression is significantly higher in gemcitabine/cisplatin-treated
patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys
genotype (4.2 months; P =.03). Other polymorphisms involved in parallel DNA repair
systems may well provide the same information, indicating a high degree of biologic
redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1)
has been linked to gemcitabine resistance in our retrospective assessment. Preliminary
findings that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and
RRM1 mRNA levels show a significantly longer survival and highlight the possibilities
of individually tailored chemotherapy.