We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)6/(TA)6 and (TA)6/(TA)7 genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai.
Surgical resection and adjuvant therapy, which mainly involves 5-fluorouracil (5-FU), irinotecan (CPT-11), oxaliplatin (LOHP) chemotherapy and recently targeted therapy, are the most common treatments of colorectal cancer (CRC).
In vitro cell proliferation, combination studies and vascular endothelial growth factor (VEGF) secretion analyses were performed on endothelial (HMVEC-d) and colorectal cancer (HT-29) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11, L-OHP and 5-FU.
The purpose of this study was to compare the sensitivity to CPT-11 in a series of CRC cell lines with either proficient or deficient MMR and to assess the mutational status of two DSB repair genes, MRE11 and RAD50, in these cell lines. hMLH1-deficient cell lines due to either epigenetic silencing or mutation showed very similar IC(50) and were four- to nine-fold more sensitive to CPT-11 than the MSS line.
Therefore, we investigated whether mRNA levels of drug targets (Topoisomerase I, TS), enzymes involved in 5-FU metabolism (DPD), in angiogenesis (EGFR, IL-8, VEGF) and in DNA-repair/drug detoxification (ERCC1, GST-P1) are associated with the clinical outcome of patients with CRC treated with first-line CPT-11 based chemotherapy.
These findings imply that the EGFR-TKI gefitinib and CPT-11 will be effective against colorectal tumor cells that express high levels of EGFR, and support clinical evaluation of gefitinib in combination with CPT-11, in the treatment of colorectal cancers.
In this report, we have studied the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice.
Irinotecan (CPT-11), a recently introduced component of a standard chemotherapy for colorectal cancer, induces in colon cancer cell lines in vitro cell cycle arrest and apoptosis.
Our in vivo study fully agrees with the predictions from the in vitro data indicating that evaluation of topoisomerase I-DNA complexes would be useful to predict the response of CRC to a treatment with CPT-11.