Oncotarget

Research Papers:

Tumor-targeting Salmonella typhimurium A1-R combined with temozolomide regresses malignant melanoma with a BRAF-V600E mutation in a patient-derived orthotopic xenograft (PDOX) model

Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Bartosz Chmielowski, Tasuku Kiyuna, Ming Zhao, Yong Zhang, Arun Singh, Michiaki Unno, Scott D. Nelson, Tara A. Russell, Sarah M. Dry, Yunfeng Li, Fritz C. Eilber and Robert M. Hoffman _

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Oncotarget. 2016; 7:85929-85936. https://doi.org/10.18632/oncotarget.13231

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Abstract

Kei Kawaguchi1,2,3, Kentaro Igarashi1,2, Takashi Murakami1,2, Bartosz Chmielowski4, Tasuku Kiyuna1,2, Ming Zhao1, Yong Zhang1, Arun Singh4, Michiaki Unno3, Scott D. Nelson5, Tara A. Russell6, Sarah M. Dry5, Yunfeng Li5, Fritz C. Eilber6, Robert M. Hoffman1,2

1AntiCancer, Inc., San Diego, CA, USA

2Department of Surgery, University of California, San Diego, CA, USA

3Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan

4Division of Hematology-Oncology, University of California, Los Angeles, CA, USA

5Department of Pathology, University of California, Los Angeles, CA, USA

6Division of Surgical Oncology, University of California, Los Angeles, CA, USA

Correspondence to:

Robert M. Hoffman, email: [email protected]

Fritz C. Eilber, email: [email protected]

Keywords: melanoma, PDOX, nude mice, orthotopic, drug-response

Received: September 14, 2016     Accepted: October 27, 2016     Published: November 09, 2016

ABSTRACT

Melanoma is a recalcitrant disease in need of transformative therapuetics. The present study used a patient-derived orthotopic xenograft (PDOX) nude-mouse model of melanoma with a BRAF-V600E mutation to determine the efficacy of temozolomide (TEM) combined with tumor-targeting Salmonella typhimurium A1-R. A melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 40 PDOX nude mice were divided into 4 groups: G1, control without treatment (n = 10); G2, TEM (25 mg/kg, administrated orally daily for 14 consecutive days, n = 10); G3, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, n = 10); G4, TEM combined with S. typhimurium A1-R (25 mg/kg, administrated orally daily for 14 consecutive days and 5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, respectively, n = 10). Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, all treatments significantly inhibited tumor growth compared to untreated control (TEM: p < 0.0001; S. typhimurium A1-R: p < 0.0001; TEM combined with S. typhimurium A1-R: p < 0.0001). TEM combined with S. typhimurium A1-R was significantly more effective than either S. typhimurium A1-R (p = 0.0004) alone or TEM alone (p = 0.0017). TEM combined with S. typhimurium A1-R could regress the melanoma in the PDOX model and has important future clinical potential for melanoma patients.


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