| Objective:Patients (48 cases) with advanced gastrointestinal cancer were treated with a therapeutic regimen based on oxaliplatin designated as FOLFOX (Oxaliplatin + CF + 5-Fu) to evaluate its clinical therapeutic effects and toxic side effects. Three pholymorphic sites in two candidate genes, C26304T (Arg194Trp) and G28152A (Arg399G1n) in XRCC1 and G19007A (Asn118Asn) in ERCC1, were studied in tested patients to explore their potential applied value.Methods:Genomic DNA was extracted from peripheral venous blood and polymorphisms in candidate genes were studied by PCR-RFLP analysis. The relationship between different genotypes and toxic side effects, general effective rate and median time to progression (TTP) were evaluated during the chemotherapeutic period.Results:1. Of all the 48 patients the general effective rate in 22 cases were evaluated. Our results showed that in this sub-group individuals inheriting different genotypes at C26304T locus in XRCC1 had no significant difference(P>0.05)in the general effective rate, 54.0%, 50.0% and 33.3% for C/T, C/C and T/T, respectively. When the whole tested group of 48 patients were evaluated no significant difference could be detected in the TTP value, 7.0 months, 6.0 months and 5.0 months for C/T, C/C and T/T, respectively. Individuals inheriting different genotypes at this locus had no significant difference in such traits measured as marrow inhibition, phlebitis, peripheral neurotoxicity, hepatotoxicity, and gastrointestinal reactions(P>0.05).2. As for the G28152A locus in XRCC1 gene, significant difference in the general effective rate was detected between patients inheriting different genotypes (P =0.033) in the sub-group of 22 cases. Individuals inheriting the G/G genotype had a much higher effective rate of 72.7% than those inheriting the G/A genotype (27.3%). In the whole 48 tested patients, individuals inheriting the G/G genotype at this polymorphic site had a significantly higher TTP value (9.0 months, P =0.039) and a much lower occurring rate of nausea and vomiting (44%, P =0.015), compared with individuals inheriting the A allele (G/A and A/A genotypes), 5.0 months and 79.2%, respectively. No significant difference was detected in other traits we measured, such as marrow inhibition, phlebitis, peripheral neurotoxicity, hepatotoxicity, and diarrhea(P>0.05).3. At the polymorphic site of G19007A in ERCC1, similar results were obtained with the homozygous G/G closely related to a significantly higher effective rate (75%, P=0.001) in the sub-group of 22 cases and a much higher TTP value (9.0 months, P=0.009) in the whole patients tested. patients inherting the heterozygous G/A genotype at this locus had an effective rate of only 20.0% in the sub-group and a TTP value of 5.0 months in the whole tested patients. In other traits as marrow inhibition, phlebitis, peripheral neurotoxicity, hepatotoxicity, and gastrointestinal reactions no significant difference was detected(P>0.05)between individuals inheriting G/G and G/A genotypes.4. Genotypic combinations of G28152A in XRCC1 and G19007A in ERCC1 were related to different effective rate in the sub-group of 22 cases with general effective rated evaluated. Individuals inheriting homozygous G allele at both loci had a significantly higher effective rate (87.5%) than those combinations inheritng the A allele at G28152A site (G/A or A/A genotype) and G/A genotype at G19007A site (14.2%, P=0.01). In the whole tested patients the average TTP value was 6.0 months, with 10.0, 5.0, 7.0, and 3.0 months for genotypic combinations of G/G+G/G, G/G+G/A, (G/A+A/A)G/G, and (G/A+A/A)G/A, respectively. Significant differences in the TTP value were detected between four different genotypic combinations(P =0.0009). Conclusion:1. Three polymorphisms in two candidate genes were detected in tested patients, C26304T(Arg194Trp)and G28152A(Arg399G1n)in XRCC1 and G19007A(Asn118Asn)in ERCC1.2. Different genotyopes at C26304T locus in XRCC1 were not closely related to the effective rate, TTP value and toxic side effects in our tested patients.3. Different genotypes at G28152A locus in XRCC1 was closely relate to effective rate, TTP value and omitting reaction in toxic side effects.4. G/G and G/A genotypes at G19007A locus in ERCC1 were closely related to the general effective rate and TTP value.5. Genotypic combinations of G28152A in XRCC1 and G19007A in ERCC1 were related to the general effective rate and TTP value in the patients treated with the therapeutic regimen of FOLFOX.We concluded that polymorphic loci in two candidate genes that associated with DNA damage, G28152A in XRCC1 and G19007A in ERCC1, were closely related to the effective rate and TTP value in the patients treated with FOLFOX regimen.
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