Recombinant Methioninase Decreased the Effective Dose of Irinotecan by 15-fold Against Colon Cancer Cells: A Strategy for Effective Low-toxicity Treatment of Colon Cancer.

BACKGROUND/AIM: Irinotecan (IRN), a topoisomerase I inhibitor and pro-drug of SN-38, is first-line treatment of colon cancer as part of FOLFIRI and FOLFOXIRI combination chemotherapy. However, IRN causes dose-limiting adverse events such as neutropenia and diarrhea. Dose reductions are sometimes required, which reduce efficacy. Recombinant methioninase (rMETase) targets the fundamental basis of cancer, methionine addiction, known as the Hoffman effect, and enhances the efficacy of numerous chemotherapy drugs. The present study determined the efficacy of rMETase when administered in combination with IRN.

MATERIALS AND METHODS

Cell viability was assessed by cultivating the HCT-116 human colorectal cancer cell line in 96-well plates at 1×10 cells per well in Dulbecco's modified Eagle's medium (DMEM). Subsequently, HCT-116 cells were treated with increasing concentrations of SN-38, the active form of IRN, ranging from 0.5 nM to 32 nM, and/or rMETase ranging from 0.125 to 8 U/ml. After treatment for 72 h, the half-maximal inhibitory concentration (IC) of SN-38 alone and rMETase alone for HCT-116 cells were determined. Using the IC concentration of rMETase, we determined the IC of SN-38 in combination with rMETase. Cell viability was determined with the cell-counting Kit-8 with the WST-8 reagent..

RESULTS

The IC of rMETase alone for the HCT-116 cells was 0.55 U/ml, and the IC of IRN (SN-38) alone was 3.50 nM. rMETase at 0.55 U/ml lowered the IC of SN-38 to 0.232 nM (p<0.0001), a 15-fold reduction.

CONCLUSION

rMETase and IRN are strongly synergistic, giving rise to the possibility of lowering the effective dose of IRN for the treatment of patients with colon cancer, thereby reducing its severe toxicity. This new strategy will allow more patients with cancer to be effectively treated with IRN.