Anti-CCNH monoclonal antibody, clone 5F22-H3-E8

New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying non-small-cell lung cancer (NSCLC) could influence chemosensitivity. In this study, we assessed whether polymorphisms in genes of nucleotide excision repair (NER) pathway, including ERCC5, ERCC6, MMS19L, CCNH, XPC, RRM1, can affect the tolerability of platinum-based chemotherapy in NSCLC patients. We used AllGloTM probe to assess genotyping and polymorphisms in 388 stage IIIB and IV NSCLC patients treated with platinum-based chemotherapy. MMS19L might be associated with the adverse events of chemotherapy in NSCLC, especially for all grade leucopenia (P=0.020), all grade jaundice (P=0.037) and all grade creatinine increasing (P=0.013). In terms of grade 3/4 adverse events, MMS19L was related with total grade 3/4 adverse events (P=0.024) and grade 3/4 thrombocytopenia (P=0.035), while RRM1 was related with total grade 3/4 adverse events (P=0.047) and grade 3/4 vomiting (P=0.046). ERCC5 was related with more infection (P=0.017). We found that some SNPs in NER pathway genes were correlated with toxicity treated with double chemotherapy in advanced NSCLC patients, especially for SNPs of MMS19L, RRM1 and ERCC5.

The combined analysis of the CCNH rs2230641 and the ABCG2 rs3114018 SNPs independently predict the development of severe oxaliplatin-induced peripheral neuropathy in early-stage colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy. This pharmacogenetic approach might improve the stratification of patients, enabling specific dosing strategies and the assessment of potential neuroprotective therapies.Oxaliplatin-based chemotherapy (CT), widely used as adjuvant therapy for stage III and selected high-risk stage II colon cancer (CC) patients, is often associated with cumulative peripheral neuropathy. Our aim is to identify single-nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin metabolism, DNA repair mechanisms, cell cycle control, detoxification or excretion pathways to predict severe (grade 2-3) oxaliplatin-induced peripheral neuropathy (OXPN) among CC patients treated with oxaliplatin and fluoropyrimidine-based adjuvant CT. Genomic DNA was extracted from formalin-fixed-paraffin-embedded peritumoral samples from 206 high-risk stage II and stage III CC patients receiving oxaliplatin-based adjuvant CT from January 2004 to December 2009. Genotyping was carried out for 34 SNPs in 15 genes using MassARRAY (SEQUENOM) technology. A total of 181 stage II-III CC patients treated with the same CT regimens were enrolled as a validation set. The rs2230641 cyclin H (CCNH) rs2230641 C/C [odd ratio (OR) = 5.03, 95% confidence interval (CI) 1.061-2.41, P = 0.042] and the ATP-binding cassette subfamily G, member 2 (ABCG2) rs3114018 A/A genotypes (OR = 2.67; 95% CI 0.95-4.41; P = 0.059) were associated with a higher risk of severe OXPN. In addition, patients harboring the combination of CCNH C/C and/or the ABCG2 rs3114018 A/A genotypes had a higher risk of grade 2-3 OXPN than those with the CCNH any T and ABCG2 any C genotypes (37.73% versus 19.42%; OR = 2.46; 95% CI 1.19-5.07; P = 0.014) in the logistic regression analysis using age, gender, adjuvant CT regimen and cumulative dose of oxaliplatin as covariates. The ability to predict severe OXPN of this combined analysis was independently validated in the second cohort (58% versus 33.33%; OR = 2.99; 95% CI 1.45-6.13; P = 0.002). Our results suggest that SNPs in CCNH and ABCG2 can modulate the development of severe OXPN among stage II-III CC patients who received oxaliplatin-based CT, thus enabling the individualization of adjuvant treatment.