Research ArticleExperimental Studies

A Gemcitabine Plus 5-Fluorouracil Combination Inhibits Gastric-Cancer Liver Metastasis in a PDOX Model: A Novel Treatment Strategy

NORIHIKO SUGISAWA, HIROTO NISHINO, TAKASHI HIGUCHI, JUN HO PARK, JUN YAMAMOTO, YOSHIHIKO TASHIRO, KEI KAWAGUCHI, MICHAEL BOUVET, MICHIAKI UNNO and ROBERT M. HOFFMAN
Anticancer Research October 2020, 40 (10) 5393-5397; DOI: https://doi.org/10.21873/anticanres.14547

Abstract

Background/Aim: We established a new patient-derived orthotopic xenograft (PDOX) model of gastric cancer liver metastasis and evaluated the efficacy of a novel combination chemotherapy, gemcitabine (GEM) plus 5-fluorouracil (5-FU), compared to a standard regimen of oxaliplatinum (L-OHP) plus 5-FU on the liver metastasis. Materials and Methods: Patient-derived gastric cancer was established in nude mice from the patient' s surgical tumor specimen. A single tumor fragment was implanted in the liver of nude mice. The mice with tumors were treated by GEM plus 5-FU or L-OHP plus 5-FU. Results: GEM plus 5-FU or L-OHP plus 5-FU significantly and similarly inhibited tumor growth on the liver compared to the untreated control (p=0.007, p=0.02, respectively). Conclusion: GEM plus 5-FU could be a novel future clinical alternative to L-OHP plus 5-FU in gastric cancer patients who cannot tolerate platinum drugs.

In gastric-cancer patients, once liver metastasis has appeared, the disease is almost always lethal. Liver metastasis of gastric cancer is mainly treated by systemic chemotherapy since surgical resection is not recommended. Systemic chemotherapy for gastric cancer is still ineffective for long-term survival. Two monoclonal antibodies for programmed cell death protein-1 (PD-1), nivolumab and pembrolizumab, recently showed significant efficacy for gastric-cancer patients in clinical trials (1-4), but immunotherapy is only effective for tumors with microsatellite instability (MSI-H) (4). For most gastric cancer patients, first-line chemotherapy comprises a combination of a fluoropyrimidine [5-fluorouracil (5-FU) or capecitabine] and a platinum drug [cisplatinum (CDDP) or oxaliplatinum (L-OHP)] (5). Both platinum drugs have a limitation for use due to toxicity. CDDP dose-dependently induces nephrotoxicity (6) and ototoxicity (7). L-OHP is less toxic than CDDP; however, L-OHP is not tolerable for some patients due to hypersensitivity reactions (8) and peripheral neuropathy (9). If gastric cancer patients have difficulty with platinum drugs, the patients are treated with 5-FU monotherapy, and if 5-FU fails, a second-line regimen with a taxane (paclitaxel or docetaxel) or irinotecan is used (10).

Gemcitabine (GEM), a synthetic pyrimidine-nucleoside prodrug, is used in various types of cancers, including breast cancer, non-small cell lung cancer, pancreatic cancer, ovarian cancer, and bladder cancer. GEM monotherapy did not show efficacy for gastric-cancer patients in previous trials (11, 12). Combination therapy with GEM and CDDP showed moderate efficacy for gastric cancer in a Phase II trial (13). Currently, there is no combination therapy with GEM recommended for gastric cancer in the clinic.

Orthotopic mouse models of cancer have many advantages over subcutaneous-implant models, which are growing ectopically under the skin (14). Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude-mouse model, which is useful for individualized treatment and precision medicine (15-21). We established the initial PDOX model of gastric cancer in 1993 (22). Our previous studies showed that orthotopic liver-metastasis and PDOX models are suitable models to evaluate drug sensitivity (23, 24).

Figure 1.
Figure 1.

Treatment protocol. The mice were randomized into 3 groups of 9 mice each.

In the present study, we compared the efficacy of the combination of L-OHP or GEM with 5-FU on a liver-metastasis PDOX model of gastric cancer and clarified whether GEM has future clinical potential for metastatic gastric cancer.

Materials and Methods

Mice. Athymic nu/nu nude mice (AntiCancer, Inc., San Diego, CA, USA) were used in this study. Mice were maintained in a barrier facility with high efficiency particulate air (HEPA)-filter at temperature 22°C and 12-h light/dark cycles. Mice were fed an autoclaved laboratory rodent diet ad libitum. Mice were observed on a daily basis and humanely sacrificed by CO2 inhalation if they met humane endpoint criteria: severe tumor burden (more than 20 mm in diameter), prostration, significant body-weight loss, difficulty breathing, rotational motion and body-temperature drop. All experiments were performed under an AntiCancer, Inc. Institutional Animal Care and Use Committee (IACUC) protocol approved for the present study, and the principles and procedures provided in the National Institutes of Health Guide for the Care and Use of Animals under Assurance Number A3873-1 (25).

Patient-derived gastric cancer. A patient diagnosed with poorly-differentiated adenocarcinoma of the stomach underwent gastrectomy in the Department of Surgery, University of California, San Diego (UCSD). A small tumor sample was obtained at the time of the surgical operation and immediately transported to the laboratory on ice. The fresh specimen was implanted into a subcutaneous pocket of nude mice. Written informed consent was provided by the patient as a part of an approved protocol by the Institutional Review Board (IRB) of UCSD.

Surgical implantation of tumor to the liver. A subcutaneous tumor of the patient-derived gastric cancer was harvested and cut into 4 mm3 fragments for surgical implantation. A 15 mm upper-midline incision was made under anesthesia by subcutaneous injection of a 0.02 ml solution of 0.25 mg ketamine, 0.38 mg xylazine, and 0.012 mg acepromazine maleate. The left lobe of liver was gently exposed, and a 7-8 mm vertical incision was made on the middle of left lobe. Then a single tumor fragment was implanted into the liver parenchyma. The wound was closed with a 6-0 nylon suture (AD Surgical, Sunnyvale, CA, USA) after confirming hemostasis (23, 24).

Figure 2.
Figure 2.

Bar graphs show relative tumor volume on day 15 for the untreated control and two treatment groups. Error bars: ±SD. *p<0.05; **p<0.01.

Treatment of gastric-cancer liver metastasis. The mice with growing tumors in the liver were randomized into 3 groups of 9 mice each when the tumor volume reached 100 mm3 and treated as follows for 2 weeks (Figure 1): Group 1 (G1): untreated control; Group 2 (G2): 5-FU (50 mg/kg, intraperitoneal (i.p.) injection, once a week) and L-OHP (6 mg/kg, i.p. injection, once a week); Group 3 (G3): 5-FU (50 mg/kg, i.p. injection, once a week) and GEM (100 mg/kg, i.p. injection, once a week). Tumor length and width were measured with electronic calipers on day 1 and 15. Tumor volume was calculated by the following formula: Tumor volume (mm3)=length (mm) × width (mm) × width (mm) × 1/2. Treatment efficacy was presented as relative tumor volume on day 15 compared to the tumor volume at the beginning of the treatment on day 1. Mouse body weight was measured twice a week. Relative body weight on day 15 compared to the body weight on day 1 was calculated.

Histological examination. All tumors were resected on day 15, and immediately fixed in 10% formalin. The resected tumors were embedded in paraffin, and then hematoxylin and eosin (H&E) staining was performed on 4 μm tissue sections. The H&E-stained slides were observed with a model BH2 microscope (Olympus Corp., Tokyo, Japan).

Statistical analysis. The data are presented as the mean±SD. One-way ANOVA with Tukey's multiple-comparison test was performed to evaluate the differences between the means. p≤0.05 is considered to be statistically significant. Statistical analyses were conducted with GraphPad Prism 7 (GraphPad Software, Inc., San Diego, CA, USA).

Results

A combination of either GEM or L-OHP plus 5-FU inhibited gastric-cancer liver metastasis. The combination of 5-FU and GEM significantly inhibited tumor growth of the liver metastasis on day 15 [relative tumor volume: 2.20±0.76 (mean±SD)] compared to the untreated control [relative tumor volume: 4.13±1.52 (mean±SD)] (p=0.007) (Figure 2). The combination of 5-FU and L-OHP also significantly inhibited the growth of liver metastasis [relative tumor volume: 2.52±1.23 (mean±SD)] compared to the untreated control (p=0.02). There was no significant difference in relative tumor volume between GEM- and L-OHP-treated groups (p=0.84).

Figure 3.
Figure 3.

Efficacy of treatment in the gastric-cancer liver-metastasis PDOX on day 15. (A) Representative images of the liver metastasis (white dotted circle) on day 15 from each group. Scale bars: 10 mm. (B) Representative images of histology with H&E staining on the liver metastasis from each group. Scale bars: 100 μm.

In the untreated control, extensive tumor growth on the liver was observed macroscopically (Figure 3A), and dense proliferation of poorly-differentiated adenocarcinoma cells was observed microscopically in H&E-stained sections (Figure 3B). Decreased tumor growth on the liver was observed macroscopically in both treatment groups of 5-FU plus L-OHP and 5-FU plus GEM, compared to the untreated control (Figure 3A). Both treatment groups decreased the number of adenocarcinoma cells. Necrotic areas were observed microscopically in H&E-stained sections for both treatment groups (Figure 3B).

Effect of treatment on body weight. All mice completed the treatment as scheduled with no obvious side-effects. There was no significant difference in relative body weight on day 15 among the untreated-control [1.04±0.03 (mean±SD)]; 5-FU plus L-OHP [1.01±0.07 (mean±SD)] (p=0.75); and 5-FU plus GEM [1.02±0.02 (mean±SD)] (p=0.85) groups (Figure 4).

Figure 4.
Figure 4.

Bar graphs show relative body weight on day 15 for the untreated-control and two treatment groups. Error bars: ±SD.

Discussion

In the present study, L-OHP or GEM in combination with 5-FU showed similar efficacy to inhibit liver-metastasis growth in a PDOX model of gastric cancer. No obvious side effects were observed with either treatment. The present study indicated that GEM combined with 5-FU can be a promising clinical regimen for liver metastasis of gastric cancer in the future.

The first PDOX model of gastric cancer was developed by our laboratory in 1993, which subsequently showed that the metastasis pattern of patients and PDOX model correlated (22, 26). The present study is the first liver-implantation PDOX model of gastric cancer. The tumor take rate in the liver was 90% allowing sufficient mice to be used for drug-sensitivity testing. The results of the present study indicate that GEM has future clinical potential for metastatic gastric cancer, which would be very valuable for patients who cannot tolerate platinum drugs.

Acknowledgements

This paper is dedicated to the memory of A.R. Moossa, M.D., Sun Lee, M.D., Professor Li Jiaxi, and Masaki Kitajima, M.D.

Footnotes

  • Authors' Contributions

    Conception and design: NS and RMH. Acquisition of data: NS and HN. Analysis and interpretation of data: NS, HN, TH, JHP, JY, YT, KK, MB, MU, and RMH. Writing, review, and/or revision of the manuscript: NS, MU, and RMH.

  • Conflicts of Interest

    The Authors declare that there are no potential conflicts of interest. AntiCancer, Inc. uses PDOX models of cancer for contract research. NS, HN, TH, JHP, JY, YT, and RMH are or were unsalaried associates of AntiCancer, Inc.

  • Received August 9, 2020.
  • Revision received August 27, 2020.
  • Accepted August 28, 2020.

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A Gemcitabine Plus 5-Fluorouracil Combination Inhibits Gastric-Cancer Liver Metastasis in a PDOX Model: A Novel Treatment Strategy
NORIHIKO SUGISAWA, HIROTO NISHINO, TAKASHI HIGUCHI, JUN HO PARK, JUN YAMAMOTO, YOSHIHIKO TASHIRO, KEI KAWAGUCHI, MICHAEL BOUVET, MICHIAKI UNNO, ROBERT M. HOFFMAN
Anticancer Research Oct 2020, 40 (10) 5393-5397; DOI: 10.21873/anticanres.14547
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