2. Academic Validation
  3. 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

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

  • Anticancer Res. 2024 Jan;44(1):31-35. doi: 10.21873/anticanres.16785.
Motokazu Sato 1 2 3 4,  Qinghong Han 1,  Yutaro Kubota 1 2,  Anton Baranov 1,  Daniel Ardjmand 1,  Kohei Mizuta 1 2,  Sei Morinaga 1 2,  Byung Mo Kang 1 2,  Noritoshi Kobayashi 3,  Michael Bouvet 2,  Yasushi Ichikawa 3,  Atsushi Nakajima 4,  Robert M Hoffman 5 2
Affiliations

Affiliations

  • 1 AntiCancer Inc., San Diego, CA, U.S.A.
  • 2 Department of Surgery, University of California, San Diego, CA, U.S.A.
  • 3 Department of Oncology, Yokohama City University School of Medicine, Yokohama, Japan.
  • 4 Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan.
  • 5 AntiCancer Inc., San Diego, CA, U.S.A.; [email protected].
PMID: 38159986 DOI: 10.21873/anticanres.16785
Abstract

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 1×103 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 (IC50) of SN-38 alone and rMETase alone for HCT-116 cells were determined. Using the IC50 concentration of rMETase, we determined the IC50 of SN-38 in combination with rMETase. Cell viability was determined with the cell-counting Kit-8 with the WST-8 reagent..

Results: The IC50 of rMETase alone for the HCT-116 cells was 0.55 U/ml, and the IC50 of IRN (SN-38) alone was 3.50 nM. rMETase at 0.55 U/ml lowered the IC50 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.

Keywords

Colon cancer; Hoffman effect; IC50; combination therapy; irinotecan; methionine; methionine addiction; synergy; toxicity.

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