Research ArticleExperimental Studies

Oral Recombinant Methioninase Overcomes Colorectal-cancer Liver Metastasis Resistance to the Combination of 5-Fluorouracil and Oxaliplatinum in a Patient-derived Orthotopic Xenograft Mouse Model

HIROMICHI OSHIRO, YASUNORI TOME, TASUKU KIYUNA, SANG NAM YOON, THINZAR M. LWIN, QINGHONG HAN, YUYING TAN, KENTARO MIYAKE, TAKASHI HIGUCHI, NORIHIKO SUGISAWA, YUKI KATSUYA, JUN HO PARK, ZHIYING ZANG, SAHAR RAZMJOOEI, MICHAEL BOUVET, BRYAN CLARY, SHREE RAM SINGH, FUMINORI KANAYA, KOTARO NISHIDA and ROBERT M. HOFFMAN
Anticancer Research September 2019, 39 (9) 4667-4671; DOI: https://doi.org/10.21873/anticanres.13648

Abstract

Background/Aim: Liver metastasis in colorectal-cancer is a recalcitrant disease. To develop precision individualized therapy of this disease, we developed a patient-derived orthotopic xenograft (PDOX) model of colorectal-cancer liver metastasis. In the present report, we evaluated the efficacy of oral recombinant methioninase (o-rMETase) in combination with 5-fluorouracil (5-FU) and oxaliplatinum (OXA) on the colorectal-cancer liver metastasis PDOX mouse model. Materials and Methods: Colorectal-cancer liver metastasis PDOX models were randomized into three groups of seven mice. Group 1, untreated control with phosphate buffered saline (PBS); Group 2, treated with 5-FU + OXA; and Group 3, treated with 5-FU + OXA + o-rMETase. Results: The colorectal-cancer liver metastasis PDOX model was resistant to 5-FU + OXA (p=0.83 at day 15 of treatment, Group 2). In contrast, the colorectal-cancer liver metastasis PDOX model was arrested by o-rMETase combined with 5-FU + OXA (p<0.01 at day 15, Group 3). No significant body-weight differences were observed among the groups. Conclusion: The combination therapy of 5-FU and OXA with o-rMETase can overcome the resistance of first line drugs for colorectal-cancer liver metastasis.

The liver is the most common site of metastases for colorectal cancer. The patients who have unresectable metastases are treated by chemotherapy and have a poor outcome (1-3).

We developed a patient-derived orthotopic xenograft (PDOX) nude mouse model for all major cancers (4). PDOX models are especially valuable to identify effective drugs for individual patients and for identification of transformational novel agents.

Cancer cells are more dependent on methionine (MET) compared to normal cells (methionine dependence/methionine addiction) (5). MET dependence may be the only known general metabolic defect in cancer (5, 6). MET restriction (MR) arrests cancer cells selectively in the S/G2-phase of the cell cycle (7-9). MET dependence is due to excess use of MET by cancer cells for transmethylation reactions (5, 10, 11). The excess use of MET in cancer is observed in the very strong signal of [11C] MET positron emission tomography imaging and has been termed the “Hoffman effect” analogous to the Warburg effect for glucose (12).

Recombinant methioninase (rMETase), a Pseudomonas putida enzyme cloned in E. coli, has been developed to arrest MET dependent cancer cells (13, 14). We have previously shown that rMETase is highly effective on melanoma, pancreatic cancer and sarcoma PDOX models (15-18). Oral rMETase (o-rMETase) was demonstrated to be more effective compared to intra-peritoneal injection of rMETase on a melanoma PDOX model and was also shown to be effective in PDOX models of melanoma, synovial sarcoma and pancreatic cancer (19-22).

Figure 1.
Figure 1.

Treatment schema. (A) A patient colorectal-cancer liver metastasis was grown orthotopically in the liver of nude mice. Treatment started on day 1st and ended on day 14th. Group 1, untreated control with PBS, i.p. (n=7); Group 2, treated with fluorouracil (5-FU) + oxaliplatin μm (OXA) (5-FU 50 mg/kg, i.p., weekly for 2 weeks, OXA 2 mg/kg, i.p., weekly for 2 weeks) (n=7); Group 3, treated with 5-FU + OXA + oral recombinant methioninase (o-rMETase) (50 unit time, twice a day, oral gavage, daily for 2 weeks) (n=7). (B) Images of the untreated and treated colorectal-cancer liver metastasis PDOX models. o-rMETase combined with 5-FU + OXA demonstrated strong efficacy on the colorectal-cancer liver-metastasis PDOX model. Scale bars are 10 mm.

In the present report, we evaluated the efficacy of o-rMETase in combination with 5-fluorouracil (5-FU) and oxaliplatin (OXA) on a drug-resistant colorectal-cancer liver metastasis PDOX model.

Materials and Methods

Mice. In the present study, we used athymic nu/nu nude mice (AntiCancer Inc., San Diego, CA, USA) between 4-6 weeks old. All animal studies were conducted with an AntiCancer Inc. Institutional Animal Care and Use Committee (IACUC)-protocol specifically approved for this study and in accordance with the principles and procedures outlined in the National Institutes of Health (NIH) Guide for the Care and Use of Animals under Assurance Number A3873-1. Procedures for housing, handling, anesthesia, feeding, and humane endpoint criteria have been previously described (20-22).

Patient-derived tumor. The tumor was derived from a patient diagnosed with colorectal-cancer liver metastasis, who had received neoadjuvant chemotherapy. The tumor was resected in the Department of Surgery, University of California, San Diego (UCSD). Written informed consent was provided by the patient, and the Institutional Review Board (IRB) of USCD approved this experiment.

Establishment of the colon-cancer liver metastasis PDOX model by surgical orthotopic implantation (SOI). A fresh sample of colorectal-cancer liver metastasis was previously obtained and transported immediately to the laboratory at AntiCancer, Inc., on wet ice. The procedures for tumor tissue fragmentation and its subcutaneously implantation in nude mice have been previously described (4, 20-22). Once the subcutaneously-implanted tumors become 10 mm in diameter (in 4 weeks), they were harvested and cut into small fragments. Anesthesia was given to mice and 1-2 cm skin incision was made on the upper abdomen through the skin, fascia and peritoneum to expose the liver. A 5 mm incision was made in the left lobe of the liver and a small tumor fragment was placed to establish the PDOX model and the wound was closed as previously described (20-22).

Figure 2.
Figure 2.

Drug efficacy on tumor volume. Bar graphs show tumor volume ratio (Tumor size on day 15 relative to tumor size at the start of treatment). Error bars show ± standard deviation. Statistical analysis was performed using Tukey-Kramer test. *p<0.05. **p<0.01. (B) Effect of treatment on body weight. Bar graphs show the body weight ratio of mice in each group on 4th day -15 relative to initiation of treatment. Actual body weight: Group 1 (untreated control): 25.41±2.92 g; Group 2 (5-FU + OXA): 24.21±0.97 g; Group 3 (5-FU + OXA + o-rMETase): 24.40±2.01 g.

Figure 3.
Figure 3.

Effect of treatment on tumor histology. (A, B). Untreated control. (C, D) 5-FU + OXA. (E, F) 5-FU + OXA + o-rMETase. Scale bars: 100 μm.

Recombinant Methionase (rMETase) production. Methods to produce recombinant L-methionine α-deamino-γ-mercaptomethane lyase [recombinant methioninase (rMETase)] have been previously described (13).

Treatment study design for the colon-cancer liver metastasis PDOX model. Colorectal-cancer liver metastasis PDOX models were randomized into three groups of seven mice. Group 1, untreated control with phosphate buffered saline (PBS), i.p. (n=7); Group 2, treated with 5-FU and OXA (5-FU 50 mg/kg, i.p., weekly for 2 weeks, OXA 2 mg/kg, i.p., weekly for 2 weeks) (n=7); Group 3, treated with 5-FU + OXA + o-rMETase (o-rMETase 50 units/time, twice a day, oral gavage, daily for 2 weeks) (n=7). Tumor length and width were measured both before and after treatment via laparotomy. Tumor volume calculation has been previously described (20-22). Data are presented as mean ± SD. In the colo-rectal-cancer liver metastasis PDOX model, treatment was evaluated on the tumor volume ratio and pathology. Adverse event were evaluated based on body weight loss.

Statistical analysis. JMP version 13.0 was used for statistical analyses. Significant differences for continuous variables were determined using the Tukey-Kramer test. Line graphs expressed average and error bars show±standard deviation. A probability value of p<0.05 was considered statistically significant.

Results and Discussion

The treatment schedule for the colorectal-cancer liver metastasis PDOX model is shown in Figure 1A. Colon-cancer liver metastasis PDOX models were randomized into three groups of seven mice. Treatment was for 14 days.

Representative tumors in each group are shown in Figure 1B. The time-course change of the tumor volume ratio is shown in Figure 2A. The colorectal-cancer liver metastasis PDOX model was resistant to the combination of 5-FU + OXA [p=0.83 at day 15 after the start of treatment (Group 2)]. In contrast, the colon-cancer liver metastasis PDOX model was arrested by o-rMETase combined with 5-FU + OXA [p<0.01 at day 15 (Group 3)].

No animal deaths in any groups were observed. Moreover, no significant body-weight differences were observed among the groups (Figure 2B). Actual mouse weight at day-15 for all groups were: Group 1 (untreated control): 25.41±2.92 g; Group 2 (5-FU + OXA): 24.21±0.97 g; Group 3 (5-FU + OXA + o-rMETase): 24.40 ± 2.01 g, respectively.

H&E-staining of tumor-tissue sections showed that the tumor tissue of the control group and the combination of 5-FU and OXA group comprised spindle-shaped cancer cells. However, the combination of 5-FU and OXA with o-rMETase group had a lower cancer-cell density and extensive necrosis compared to the control and the combination of 5-FU and OXA group. The high efficacy of combination therapy with o-rMETase is shown histologically (Figure 3).

In the present study, the colon-cancer liver metastasis PDOX mouse model was resistant to the combination of 5-FU and OXA, and o-rMETase was able to overcome this resistance.

Our previous studies have shown that o-rMETase had significant efficacy on melanoma, synovial sarcoma and pancreatic cancer PDOX models. The present study demonstrates that combination therapy with o-rMETase can overcome first-line drug resistance of colon-cancer liver metastasis and is a promising clinical strategy for the disease.

Most cancer cells are addicted on MET for their survival. MET-dependent cells synthesize a normal amount of MET; however, they are deficient in S-adenosylmethionine (AdoMET) (11, 22, 23). Under MET restriction, MET-dependent cancer cells contain low amounts of free MET. It has been suggested that the high MET requirement of cancer cells is due to increased rates of transmethylation compared to normal cells. MET restriction selectively arrests cancer cells in S/G2 Phase the cell cycle, thereby blocking cancer cell proliferation (11, 22, 23). MET restriction therefore sensitizes cancer cells to cytotoxic therapy (24-26). Recently tumor initiating cells were found to be highly MET-dependent (27). Thus, o-rMETase can be potentially used for the treatment of cancer.

Acknowledgements

The paper is dedicated to the memory of AR Moossa, MD; Sun Lee, MD; Professor Li Jiaxi and Masaki Kitajima, MD.

Footnotes

  • Authors' Contributions

    Conception and design HO, TH and RMH. Acquisition of data: HO, YT, TK, SNY, TML, QH, YT, KM, TH, NS, YK, JHP, and ZZ, SR. Analysis and interpretation of data: HO, YT, TK, SNY, TML, QH, YT, KM, TH, NS, YK, JHP, ZZ, SR, MB, BC, SRS, FK, KN and RMH. Writing, review, and/or revision of the manuscript: HO, RMH, and SRS.

  • Conflicts of Interest

    AntiCancer Inc. uses PDOX models for contract research. QH and YT are employees of AntiCancer Inc. HO, SNY, QH, YT, KM, TH, NS, YK, JHP, ZZ, SR and RMH are or were unsalaried associates of AntiCancer Inc. There are no other competing financial interests.

  • Received July 11, 2019.
  • Revision received July 17, 2019.
  • Accepted July 18, 2019.

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Oral Recombinant Methioninase Overcomes Colorectal-cancer Liver Metastasis Resistance to the Combination of 5-Fluorouracil and Oxaliplatinum in a Patient-derived Orthotopic Xenograft Mouse Model
HIROMICHI OSHIRO, YASUNORI TOME, TASUKU KIYUNA, SANG NAM YOON, THINZAR M. LWIN, QINGHONG HAN, YUYING TAN, KENTARO MIYAKE, TAKASHI HIGUCHI, NORIHIKO SUGISAWA, YUKI KATSUYA, JUN HO PARK, ZHIYING ZANG, SAHAR RAZMJOOEI, MICHAEL BOUVET, BRYAN CLARY, SHREE RAM SINGH, FUMINORI KANAYA, KOTARO NISHIDA, ROBERT M. HOFFMAN
Anticancer Research Sep 2019, 39 (9) 4667-4671; DOI: 10.21873/anticanres.13648
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