Combination therapy with F5/35 fiber chimeric conditionally replicative adenoviruses expressing IL-24 enhances the antitumor effect of temozolomide against melanoma

Cancer Med. 2018 Dec;7(12):5928-5942. doi: 10.1002/cam4.1843. Epub 2018 Nov 8.

Abstract

Background: Temozolomide (TMZ) is widely used to treat melanoma; however, response rates to TMZ are low because of rapid and frequent resistance. Conditionally, replicative adenoviruses (CRAds) are an effective and promising approach. The receptor for adenovirus is coxsackie-adenovirus receptor (CAR), which is poorly expressed in most cells. However, CD46, which is the receptor of species B adenoviruses (Ads), is highly expressed in many cells.

Methods: We constructed CRAd F5/35-ZD55-IL-24, which uses the viral receptors CAR and CD46 for entry into cells. We investigated the antitumor effect of F5/35-ZD55-IL-24 in combination with TMZ to treat melanoma in vitro and in vivo.

Results: The \results indicated that F5/35-ZD55-IL-24 in combination with TMZ produced additive or synergistic antitumor and pro-apoptotic effects in melanoma cells. The combination of F5/35-ZD55-IL-24 and TMZ significantly inhibited the growth of melanoma in vivo. In addition, the antitumor effect of F5/35-ZD55-IL-24 was superior to that of ZD55-IL-24 and ZD55-IL-24 combined with TMZ.

Conclusions: The use of F5/35-ZD55-IL-24 in conjunction with TMZ is a promising approach for anti-melanoma therapy. Our results indicated that F5/35-ZD55-IL-24 in combination with TMZ produced additive or synergistic antitumor effect and pro-apoptotic effect in melanoma cells highly expressed CD46. The combination of F5/35-ZD55-IL-24 and TMZ significantly inhibited the growth of melanoma in vivo. We also found the antitumor effect of F5/35-ZD55-IL-24 was superior to ZD55-IL-24, the combination of F5/35-ZD55-IL-24 and TMZ had a more significant antitumor effect than ZD55-IL-24 combining with TMZ.

Keywords: CRAd; F5/35; conditionally replicative adenovirus; interleukin 24; melanoma; temozolomide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Cell Line
  • Combined Modality Therapy
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Interleukins / genetics*
  • Interleukins / metabolism
  • Male
  • Melanoma / metabolism
  • Melanoma / pathology
  • Melanoma / therapy*
  • Membrane Cofactor Protein
  • Mice, Inbred BALB C
  • Mice, Nude
  • Temozolomide / pharmacology
  • Temozolomide / therapeutic use*
  • Tumor Burden

Substances

  • Antineoplastic Agents, Alkylating
  • CD46 protein, human
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Interleukins
  • Membrane Cofactor Protein
  • interleukin-24
  • Temozolomide