Enhanced antitumor efficacy of a novel oncolytic adenovirus combined with temozolomide in the treatment of melanoma in vivo.

Abstract

PURPOSE:

The aim of this study was to investigate the effect of Ki67-ZD55-IL-24 with temozolomide (TMZ) against melanoma in mice.

METHODS:

Seventy-eight mice with subcutaneous injection of A375 cells (2 × 10(6)) into the right flank were randomized to receive phosphate buffered saline (PBS), Ki67-ZD55, Ki67-ZD55-IL-24, TMZ, TMZ + Ki67-ZD55, and TMZ + Ki67-ZD55-IL-24. Six mice were killed in each group 10 days after intervention for detecting IL-24 mRNA and protein expression. The remaining mice were monitored to draw the body weight change curve and tumor growth curve, and killed 30 days after intervention. Tumors were excised and weighted. The morphology of tumor tissues was determined by hematoxylin and eosin (HE) staining, and the apoptosis index and rate of apoptotic cells were determined by TUNEL assay and AnnexinV-FITC/PI double staining, respectively.

RESULTS:

The Ki67-ZD55-IL-24-treated group generated much more reactive oxygen species than the untreated group. There was no significant difference in IL-24 expression between Ki67-ZD55-IL-24 and TMZ + Ki67-ZD55-IL-24 groups. Immunohistochemical analysis and Western blot revealed that both the Ki67-ZD55 and Ki67-ZD55-IL-24 could significantly reduce the expression of MGMT. Toxicity assessments demonstrated that mice in the three groups that received TMZ exhibited significant body weight loss following treatment. HE staining showed that TMZ + Ki67-ZD55-IL-24 group had much fewer karyokinesis in the tumors, compared with other groups. The apoptosis index of tumor tissues and the rate of apoptotic cells were significantly higher in TMZ + Ki67-ZD55-IL-24 group than in other groups (all P < 0.05).

CONCLUSIONS:

These findings indicate this novel strategy holds promising potentials for treatment of malignant melanoma.

• Authors: Guan Jiang, Chao Sun, Rong-Hua Li, Zhi-Ping Wei, Jun-Nian Zheng, Yan-Qun Liu
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 141 Issue 1 Pg. 75-85 (Jan 2015) ISSN: 1432-1335 [Electronic] Germany
• PMID: 25103017 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Interleukins
• Ki-67 Antigen
• RNA, Messenger
• Reactive Oxygen Species
• Tumor Suppressor Proteins
• interleukin-24
• Dacarbazine
• DNA Modification Methylases
• MGMT protein, mouse
• DNA Repair Enzymes
• Temozolomide

Topics

• Adenoviridae (genetics)
• Animals
• Antineoplastic Agents, Alkylating (therapeutic use)
• Apoptosis
• Blotting, Western
• Cell Proliferation
• Combined Modality Therapy
• DNA Modification Methylases (genetics, metabolism)
• DNA Repair Enzymes (genetics, metabolism)
• Dacarbazine (analogs & derivatives, therapeutic use)
• Flow Cytometry
• Genetic Therapy
• Humans
• Immunoenzyme Techniques
• Interleukins (genetics)
• Ki-67 Antigen (genetics, metabolism)
• Male
• Melanoma (genetics, pathology, therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Oncolytic Virotherapy
• RNA, Messenger (genetics)
• Reactive Oxygen Species (metabolism)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Temozolomide
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (genetics, metabolism)
• Xenograft Model Antitumor Assays