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ORIGINAL ARTICLE
Ahead of print publication  

Efficacy of vorinostat-sensitized intraperitoneal radioimmunotherapy with 64Cu-labeled cetuximab against peritoneal dissemination of gastric cancer in a mouse model


1 National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
2 Nihon Medi-Physics Co., Ltd., Tokyo, Japan

Date of Submission30-Jan-2020
Date of Decision28-May-2020
Date of Acceptance22-Jun-2020
Date of Web Publication03-Nov-2020

Correspondence Address:
Yukie Yoshii,
National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage, Chiba 263-8555
Japan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_124_20

 > Abstract 


Background: Gastric cancer is a common cause of cancer-related death worldwide, and peritoneal dissemination is the most frequent metastatic pattern of gastric cancer. However, the treatment of this disease condition remains difficult. It has been demonstrated that intraperitoneal radioimmunotherapy (ipRIT) with 64Cu-labeled cetuximab (anti-epidermal growth factor receptor antibody; 64Cu-cetuximab) is a potential treatment for peritoneal dissemination of gastrointestinal cancer in vivo. Recent preclinical and clinical studies have also shown that a histone deacetylase inhibitor, vorinostat, effectively sensitized gastrointestinal cancer to external radiation.
Aim: In the present study, we examined the efficacy of the combined use of vorinostat, as a radiosensitizer during ipRIT with 64Cu-cetuximab in a peritoneal dissemination mouse model with human gastric cancer NUGC4 cells stably expressing red fluorescent protein.
Methods: The mouse model was treated by ipRIT with 64Cu-cetuximab plus vorinostat, each single treatment, or saline (control). Side effects, including hematological and biochemical parameters, were evaluated in similarly treated, tumor-free mice.
Results: Coadministration of ipRIT with 64Cu-cetuximab + vorinostat significantly prolonged survival compared to control and each single treatment. No significant toxicity signals were observed in all treatment groups.
Conclusions: Our data suggest that vorinostat is a potentially effective radiosensitizer for use during the treatment of peritoneal dissemination of gastric cancer by ipRIT with 64Cu-cetuximab.

Keywords: 64Cu-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1 (15),11,13-triene-3,6,9-triacetic acid-cetuximab, gastric cancer, peritoneal dissemination, vorinostat



How to cite this URL:
Tachibana T, Yoshii Y, Matsumoto H, Zhang MR, Nagatsu K, Hihara F, Igarashi C, Sugyo A, Tsuji AB, Higashi T. Efficacy of vorinostat-sensitized intraperitoneal radioimmunotherapy with 64Cu-labeled cetuximab against peritoneal dissemination of gastric cancer in a mouse model. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 3]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299882




 > Introduction Top


Gastric cancer is the second most common cause of cancer-related deaths worldwide.[1] Peritoneal dissemination is reported as the most frequent pattern of metastasis in gastric cancer; however, there are no effective therapies.[1] Hence, the prognosis for gastric cancer with peritoneal dissemination is extremely poor, and the mean overall survival of patients with this disease is reported to be only 4 months after diagnosis.[2] Therefore, the development of effective therapies against this disease is urgently needed.

We have reported that intraperitoneal radioimmunotherapy (ipRIT) with 64 Cu-labeled cetuximab (an anti-epidermal growth factor receptor [EGFR] antibody,64 Cu-cetuximab) is a potential treatment for peritoneal dissemination of gastrointestinal cancers in mouse models.[3] Furthermore, intraperitoneal (IP) injection of 64 Cu-cetuximab induced higher and more rapid accumulation of the drug in peritoneal dissemination than that achieved after intravenous injection and resulted in prolonged survival of the mouse model.[3] To date, many studies using cetuximab labeled with radioisotopes including 90 Y and 64 Cu have been conducted.[4],[5],[6],[7],[8],[9],[10],[11] A series of these studies has shown that radiolabeled cetuximab binds to EGFR on the surface of the tumor cells with high affinity, after which some become internalized by the cells. The cetuximab labeled with therapeutic radioisotopes either bound to, or inside, the tumor cells can then induce cytotoxicity by causing DNA double-strand breaks.[4],[5],[6],[7],[8],[9],[10],[11] In case of 64 Cu (β+ decay 0.653 MeV, 17.4%; β decay, 0.574 MeV, 40%; electron capture, 42.6%), it emits β particles and high-linear energy transfer Auger electrons to damage tumor DNA.[12],[13] Particularly, after internalization of 64 Cu-cetuximab, a portion of 64 Cu activity was reportedly delivered from the cytoplasm to the nuclei as cancer cells naturally maintain elevated Cu levels in the cell nuclei and cytoplasm compared to normal tissues, for use in cell proliferation and survival.[14],[15],[16],[17],[18],[19] Hence,64 Cu translocated to the nuclei can facilitate the effect of radioimmunotherapy with 64 Cu-cetuximab. Furthermore,64 Cu is a practical radionuclide for clinical application since it can be easily produced on a large scale.[20] Considering this background and that EGFR positivity is high in gastric cancer patients,[21],[22],[23] ipRIT with 64 Cu-cetuximab could be a promising therapy for the treatment of peritoneal dissemination of gastric cancer; however, further investigations are warranted to explore more effective use of this therapy.

A histone deacetylase (HDAC) inhibitor, vorinostat, is a potential radiosensitizer as it has been reported to improve the efficacy of external radiation in recent preclinical and clinical studies in many types of cancers, including gastric cancer.[24],[25] This improved efficacy occurs by perturbing the repair mechanism of DNA double-strand breaks, including DNA-repair signaling and pathways.[24],[26] Vorinostat was a more effective sensitizer for external radiation than the conventional radiosensitizer capecitabine in an in vivo study.[27] Phase I clinical trials combining vorinostat with external radiation have shown the safety of this therapy.[28],[29] Previous radioimmunotherapy studies have shown that the use of radiosensitizers results in improved treatment efficacy by overcoming the radioresistance of tumors.[30],[31]

Based on these lines of evidence, we hypothesized that a combined use of ipRIT with 64 Cu-cetuximab (for damaging tumor DNA) and vorinostat (a sensitizer for inhibiting the DNA repair mechanism) would be effective in the treatment of peritoneal dissemination of gastric cancer. The aim of this study is to examine the efficacy and safety of combining ipRIT with 64 Cu-cetuximab and vorinostat in vivo. For the in vivo treatment study, we used a mouse model of peritoneal dissemination of human gastric cancer NUGC4 cells stably expressing red fluorescent protein (NUGC4-RFP cells) in this study.


 > Materials and Methods Top


Cell cultivation

Human gastric cancer NUGC4-RFP cells were obtained from AntiCancer (KBNO112_02, San Diego, CA, USA). The cells were incubated in Roswell Park Memorial Institute-1640 medium (189-02025, WAKO, Osaka, Japan) supplemented with 10% fetal bovine serum in a humidified atmosphere of 5% CO2 at 37°C. Exponentially growing cells were used in the study and were detached from the plates using trypsin. The number of viable cells was determined using the Trypan blue dye-exclusion method.

Preparation of 64Cu-labeled cetuximab

Cetuximab was obtained from Merck Serono (Darmstadt, Germany), and 64 Cu was produced and purified using previously published methods.[20] Cetuximab was 64Cu labeled using 3, 6, 9, 15-tetraazabicyclo[9.3.1]pentadeca-1 (15), 11, 13-triene-3, 6, 9-triacetic acid (PCTA) as the chelator, since this process showed high radiolabeling yield and in vitro serum stability in previous studies.[3],[32] 64Cu-PCTA-cetuximab was prepared according to a previously reported method,[3] with a specific activity of 1.7 GBq/mg. The injected protein dose of 64 Cu-PCTA-cetuximab was adjusted to 20 μg per mouse by adding an unlabeled antibody as reported previously.[3]

Peritoneal dissemination mouse model

The animals were maintained and handled in accordance with the recommendations of the National Institute of Health and the institutional guidelines. The study protocols were approved by the Institutional Animal Ethics Committee. For the in vivo treatment study, the mouse model of NUGC4-RFP peritoneal dissemination that was established in our previous study [3] was used. Briefly, the model was established in female BALB/c nude mice (6-week-old mice with uniform body weight) obtained from the Japan SLC (Shizuoka, Japan). The animals were fed a purified diet (AIN-93M, TestDiet, St. Louis, MO, USA). Before the experiments, the mice were acclimatized for at least 1 week and then injected IP with 5 × 106 NUGC4-RFP cells suspended in 500 μl phosphate-buffered saline. On day 7 after inoculation (treatment day 0), the in vivo treatment study was performed. Before the treatment study, a laparotomy was performed to observe tumor development using a stereoscopic fluorescence microscope (MZ16F, Leica, Wetzlar, Germany) equipped with a camera system (DFC310FX, Leica).

Histopathology and immunohistochemistry

The tumors were collected for histopathology and immunohistochemistry from the mouse model of NUGC4-RFP peritoneal dissemination. Harvested tumors were fixed in 10% buffered formalin (Sigma Aldrich, St. Louis, MO, USA) and paraffin embedded, and then, 6 μm-thick sections were cut according to the standard histological procedures. For histopathology, routine hematoxylin and eosin staining was performed with deparaffinized sections. Immunohistochemical staining for EGFR was performed with deparaffinized sections according to previously described methods.[33] Primary antibodies against EGFR (1:50; Cell Signaling Technology, Danvers, MA, USA) and a rabbit IgG isotype (negative control) were used. Immunohistochemically stained sections were counterstained with hematoxylin, and the images were obtained using an Olympus BX43 microscope with a DP21 camera system (Olympus, Tokyo, Japan).

In vivo treatment study

The modeled mice were randomly divided into the following four groups of seven animals each: (1) control, (2)64 Cu-cetuximab only, (3) vorinostat only, and (4)64 Cu-cetuximab + vorinostat. The mice were injected IP with 22.2 MBq 64 Cu-cetuximab (64 Cu-cetuximab only and 64 Cu-cetuximab + vorinostat groups) or saline (control and vorinostat only groups) on day 0. The injected dose and preparation method of the 64 Cu-cetuximab solution were selected and performed based on a previous study.[34] One hour before administration of 64 Cu-cetuximab, 150 mg/kg vorinostat (vorinostat only and 64 Cu-cetuximab + vorinostat groups) or saline (control and 64 Cu-cetuximab only groups) was administered IP. The dose, route, and timing of vorinostat administration were based on a previous study.[3],[24] For the in vivo study, vorinostat was dissolved in 10 μl dimethyl sulfoxide and then further diluted with 90 μl saline just before administration. The general condition and body weight of the mice were monitored weekly. The mice were sacrificed at the humane endpoint, defined as a noticeable extension of the abdomen, development of ascites, or body weight loss >20%. Median survival time (MST) was determined, and prolonged survival time was calculated as (MST [treatment group] – MST [control group]) [Table 1].
Table 1: Analysis on median survival time and prolonged median survival time using in vivo treatment study using NUGC4 cells stably expressing red fluorescent protein peritoneal disseminated mice

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Measurement of hematological and biochemical parameters

To evaluate the side effects, hematological and biochemical parameters were measured in tumor-free mice similarly treated to those used in the in vivo treatment study (n = 4/group: control,64 Cu-cetuximab only, vorinostat only,64 Cu-cetuximab + vorinostat groups). Hematological parameters were measured on day 0 (just before 64 Cu-cetuximab injection) and on day 7, 14, 21, and 35, using blood collected from the tail vein. The concentrations of white blood cells (WBCs), red blood cells (RBCs), and platelets (PLTs) were determined using a hematological analyzer (Celltac MEK-6458, Nihon Kohden). Biochemical parameters were measured on day 35 in the mouse plasma isolated from blood collected by cardiac puncture. The levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), and alkaline phosphatase (ALP) were determined to assess liver function. Blood urea nitrogen (BUN) and creatinine (CRE) levels were determined to assess kidney function. Amylase (AMYL) and lipase (LIP) levels were determined to assess pancreatic function. Biochemical parameters were measured using a blood biochemistry analyzer (Dri-Chem 7000VZ Fuji Film).

Statistical analysis

Data are expressed as means ± standard deviation. P values were calculated using the Kruskal–Wallis test with Steel–Dwass post hoc test for comparisons among multiple groups. Differences in survival were evaluated using the log-rank test. All statistical analyses were conducted at a significance level of P < 0.05.


 > Results Top


In vivo treatment study with NUGC4 cells stably expressing red fluorescent protein peritoneal dissemination mouse model

Before the in vivo treatment study, tumor development in the mouse model used in this study was observed using a fluorescence microscope, and the images are shown in [Figure 1]. Peritoneal disseminations were observed in the mouse model. Isolated NUGC4-RFP tumors showed overexpression of EGFR [Figure 2]. Survival was significantly higher in the 64 Cu-cetuximab + vorinostat group than in the control,64 Cu-cetuximab only, and vorinostat only groups [P = 0.00168, P = 0.0281, and P = 0.0046, respectively, [Figure 3]. The 64 Cu-cetuximab only group had significantly prolonged survival compared to the control group (P = 0.0291), which was consistent with our previous study.[3] MST values were 14, 20, 17, and 31 days for the control,64 Cu-cetuximab only, vorinostat only, and 64 Cu-cetuximab + vorinostat groups, respectively [Table 1].64 Cu-cetuximab + vorinostat group showed higher MST by 17 days than that of the control group. In contrast, the MST of the 64 Cu-cetuximab only and vorinostat only groups was higher by only 7 and 3 days, respectively, than that of the control group [Table I]. This indicated that the MST of the 64 Cu-cetuximab + vorinostat group was prolonged more than the sum of the prolongation of the 64 Cu-cetuximab only and vorinostat only groups, which suggests that coadministration of 64 Cu-cetuximab and vorinostat showed synergistically higher survival than that for each single treatment. The general conditions were unperturbed and the body weight loss >20% of the initial body weight was not observed in any treatment group until the endpoint. The body weight changes throughout the study for each group are shown in [Figure 4].
Figure 1: Observation of mouse model of peritoneal dissemination gastric cancer induced by NUGC4 cells stably expressing red fluorescent protein. Representative images of NUGC4 cells stably expressing red fluorescent protein tumors in peritoneal dissemination mouse model detected using stereoscopic fluorescence microscope. Tumors are shown by yellow arrowheads. Bright.field, red fluorescence, and merged views are shown in the left, middle, and right of image, respectively

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Figure 2: Representative images of immunohistochemical staining for epidermal growth factor receptor expression in tumors induced by NUGC4 cells stably expressing red fluorescent protein. Images of immunohistochemical staining for epidermal growth factor receptor and negative control in NUGC4 cells stably expressing red fluorescent protein tumors and hematoxylin and eosin staining. Images of staining for epidermal growth factor receptor, negative control, and hematoxylin and eosin are shown in the left, middle, and right of the image, respectively

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Figure 3: Survival curves for the in vivo treatment study with NUGC4 cells stably expressing red fluorescent protein peritoneal disseminated mice. Kaplan–Meier survival curve for control (blue line), 64Cu-labeled cetuximab only (purple dotted line), vorinostat only (green dashed line), and 64Cu-labeled cetuximab + vorinostat (red dashed line) groups (n = 7/group). a, b, c: Different letters indicate significant difference (P < 0.05)

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Figure 4: Body weight changes in the in vivo treatment study with NUGC4 cells stably expressing red fluorescent protein peritoneal disseminated mice. Body weights that were measurable up to the endpoint during the in vivo treatment study as shown in Figure 3

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Side effects of 64Cu-labeled cetuximab + vorinostat

To evaluate the side effects, hematological and biochemical parameters were also measured in tumor-free mice similarly treated to the mice in the control,64 Cu-cetuximab only, vorinostat only, and 64 Cu-cetuximab + vorinostat groups in the in vivo treatment study. No significant reduction in the number of WBCs, RBCs, and PLTs, which would be indicative of hematological toxicity, was observed at any examined time point in all treatment groups [Figure 5]. No adverse effects on biochemical parameters were observed in any treatment groups: There was no significant increase the GOT, GPT, and ALP for liver function; BUN and CRE for kidney function; and AMYL and LIP for pancreas function after treatments [Figure 6]. These results indicated that no significant toxicity signals were observed in the coadministration of 64 Cu-cetuximab and vorinostat in mice.
Figure 5: Hematological toxicity in NUGC4 cells stably expressing red fluorescent protein peritoneal disseminated mice. Hematological examination of tumor free mice of four groups (control, 64Cu-labeled cetuximab only, vorinostat only, and 64Cu-labeled cetuximab + vorinostat). White blood cells, red blood cells, and platelet numbers on day 0, 7, 14, 21, and 35 after injection are shown. Values are means ± standard deviation. No significant reduction occurred after treatment in any hematological parameters compared to day 0 in each group

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Figure 6: Biochemical examinations of NUGC4 cells stably expressing red fluorescent protein peritoneal disseminated mouse model. Biochemical parameters on day 35 after injection. GOT = Glutamate oxaloacetate transaminase, GPT = Glutamate pyruvate transaminase, ALP = Alkaline phosphatase for liver function, BUN = Blood urea nitrogen; CRE = Creatinine for kidney function, AMYL = Amylase, LIP = Lipase for pancreas function. Values are means ± standard deviation. No significant increase was observed after treatment in any biochemical parameters in each group compared to control

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 > Discussion Top


In this study, we demonstrated that combining ipRIT with 64 Cu-cetuximab and vorinostat improved survival in a mouse model of peritoneal dissemination of human gastric cancer with NUGC4-RFP cells. In addition, we demonstrated that coadministration of vorinostat alongside ipRIT with 64 Cu-cetuximab resulted in no major adverse events. Based on these results, vorinostat-sensitized ipRIT with 64 Cu-cetuximab would be an effective therapeutic strategy for the treatment of peritoneal dissemination of gastric cancer.

Peritoneal dissemination of gastrointestinal cancers, including gastric cancer, are often treated by systemic chemotherapy with anticancer drugs, such as 5-fluorouracil, gemcitabine, and cisplatin, but the effect is limited.[35],[36],[37],[38] IP-administered chemotherapy with the anticancer drugs has also been tested due to its ability to increase drug accumulation in tumors;[39] however, it has only moderately improved survival.[40],[41],[42] Our previous study have demonstrated that IP-administered 64 Cu-cetuximab effectively suppressed peritoneal dissemination of gastrointestinal cancers in the mouse models by facilitating drug accumulation in tumors and that this therapeutic effect was better than that of IP chemotherapy with gemcitabine.[3],[34] This indicated that ipRIT with 64 Cu-cetuximab is a promising treatment for peritoneal dissemination. In addition, the present study demonstrated that coadministration of vorinostat alongside ipRIT with 64 Cu-cetuximab synergistically improved survival compared to the single treatment of the ipRIT with 64 Cu-cetuximab. This observation suggested that the use of vorinostat could be worthwhile to be recommended to synergistically enhance the therapeutic effect in the therapeutic strategy of ipRIT with 64 Cu-cetuximab. We observed that the coadministration of vorinostat in ipRIT with 64 Cu-cetuximab did not cause any major side effects while showed synergistical increase of survival. This indicates that vorinostat would be an ideal radiosensitizer for the ipRIT with 64 Cu-cetuximab because it can make the tumor more radioresponsive without toxicity. Vorinostat, as an HDAC inhibitor, has been reported to be an effective sensitizer in combination with external radiation by inhibiting the repair mechanism of DNA double-strand breaks.[24],[25],[26] Thus, inhibiting the repair mechanism of DNA double-strand breaks may be a reasonable mechanism of the effect of vorinostat as a sensitizer during ipRIT with 64 Cu-cetuximab. Further in vitro and in vivo studies would be required to show the mechanism of the therapeutic effect. A recent phase I clinical trial has shown the tolerability of vorinostat in combination with external radiation inpatients, indicating the potential clinical applicability of vorinostat as a radiosensitizer.[28],[29] Nevertheless, for clinical application of vorinostat specifically with 64 Cu-cetuximab ipRIT, additional preclinical and clinical studies are necessary to determine safety.

This study was performed using the peritoneal dissemination mouse model that possessed small tumors [Figure 1]. For large solid tumors, the effectiveness of radioimmunotherapy is generally limited due to the poor penetration of immunoconjugates into poorly perfused tumor masses and the short radiation range of radioisotopes.[43],[44] Similarly, the therapeutic efficacy of ipRIT with 64 Cu-cetuximab would be limited in cases with small lesions rather than large tumor masses, since 64 Cu also exhibits a short radiation range in the tissues (mean range <1 mm; 0.02–10 μm for Auger electrons).[3],[13],[45] Given these physical characteristics of 64 Cu, the combined use of cytoreductive surgery to remove large tumor masses and vorinostat-sensitized ipRIT with 64 Cu-cetuximab to treat residual small lesions would be a practical option in the clinical settings.

The present study has some limitations that are worth mentioning. First, we administered a single dose of vorinostat before ipRIT with 64 Cu-cetuximab, similar to animal studies which administer a single dose before external irradiation.[24] However, radiotherapy is performed several times with single administration of vorinostat before each irradiation. Further evaluation of the efficacy of multiple doses of 64 Cu-cetuximab with coadministration of vorinostat would be necessary in future studies. Moreover, repeated administration of vorinostat is worth investigating because tumors showed the lasted retention of 64 Cu-cetuximab.[3] Second, in the present study, vorinostat was IP administered, using the similar administration route to the animal study of external irradiation.[24] For clinical application, optimization of dose, route, and timing of vorinostat administration would be needed. Third, there may be discrepancies between mice and humans in the immunoreactivity of 64 Cu-cetuximab. Therefore, careful toxicological evaluation of this treatment in humans is necessary.


 > Conclusion Top


We demonstrated that vorinostat enhanced the therapeutic effectiveness of ipRIT with 64 Cu-cetuximab against gastric cancer peritoneal dissemination in a mouse model. In addition, coadministration of vorinostat alongside ipRIT with 64 Cu-cetuximab showed little toxicity. These data suggest that vorinostat-sensitized ipRIT with 64 Cu-cetuximab is a promising treatment option for peritoneal dissemination of gastric cancer.

Acknowledgments

We would like to thank Mr. Hisashi Suzuki (National Institute of Radiological Sciences, Japan) for providing the radiopharmaceuticals. We would like to thank Editage (www.editage.com) for English language editing.

Financial support and sponsorship

This work was supported by Grants-in-Aid for Scientific Research C (Grant Number 25461863) from the Japanese Society for the Promotion of Science, Japan to Y.Y.

Conflicts of interest

Hiroki Matsumoto is an employee of Nihon Medi-Physics Co., Ltd.



 
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