A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy

Our plain-English summary of A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy, by Y. Watanabe, T. Kojima, S. Kagawa, et al (Oncogene, 2010).

The study

• Authors: Y. Watanabe, T. Kojima, S. Kagawa, F. Uno, Y. Hashimoto, S. Kyo, H. Mizuguchi, N. Tanaka, H. Kawamura, D. Ichimaru, Y. Urata, T. Fujiwara
• Journal: Oncogene
• Published: 2010;29(8):1145-54
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that is related to asbestos exposure. MPM is characterized by rapid and diffuse local growth in the thoracic cavity, and it has a poor prognosis because it is often refractory to conventional therapy. Although MPM is an extraordinarily challenging disease to treat, locoregional virotherapy may be useful against this aggressive disease because of the accessibility by intrapleural virus delivery. In this study, we show that telomerase-specific, replication-selective adenovirus OBP-301 can efficiently infect and kill human mesothelioma cells by viral replication. Intrathoracic administration of virus significantly reduced the number and size of human mesothelioma tumors intrathoracically implanted into nu/nu mice. A high-definition, fluorescence optical imaging system with an ultra-thin, flexible fibered microprobe clearly detected intracellular replication of green fluorescent protein-expressing oncolytic virus in intrathoracically established mesothelioma tumors. As the extracellular matrix (ECM) may contribute to the physiological resistance of a solid tumor by preventing the penetration of therapeutic agents (including oncolytic viruses), we also examined whether the co-expression of heparanase, an endoglucuronidase capable of specifically degrading heparan sulfate, that influences the physiological barrier to macromolecule penetration, can modify the permeability of the ECM, resulting in profound therapeutic efficacy. Co-injection of OBP-301 and a replication-defective adenovirus (Ad-S/hep)-expressing heparanase resulted in more profound antitumor effects without apparent toxicity in an orthotopic pleural dissemination model. Our results suggest that intrathoracic dual virotherapy with telomerase-specific oncolytic adenovirus in combination with heparanase-expressing adenovirus may be efficacious in the prevention and treatment of pleural dissemination of human malignant mesothelioma.

In plain English

This laboratory and animal study tested a telomerase-specific, replication-selective adenovirus (OBP-301) against human malignant pleural mesothelioma, a tumour the authors describe as related to asbestos exposure in the introduction; asbestos exposure itself was not studied. Four human mesothelioma cell lines (H2052, H2452, H28, 211H) all expressed coxsackie and adenovirus receptor and detectable hTERT messenger RNA, and all were killed by OBP-301 in a dose-dependent way, with infection at a multiplicity of infection of 10 sufficient to cause cell lysis within 3 days. In athymic nu/nu mice given H2452 cells into the thoracic space, two intrathoracic injections of 1 x 10 to the 8th plaque-forming units of OBP-301 reduced the number and weight of disseminated tumour nodules compared with control virus dl312 or saline, while 1 x 10 to the 7th had no apparent effect; complete eradication of nodules was not achieved. Adding heparanase-expressing adenovirus Ad-S/hep deepened virus penetration in tumour spheroids and further reduced tumour weights; five of seven combination-treated mice survived 12 weeks versus one of seven given OBP-301 alone.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study in human mesothelioma cell lines and tumour spheroids with experiments in athymic nu/nu mice (orthotopic pleural dissemination model)
• Who was studied: Four human mesothelioma cell lines (H2052, H2452, H28, 211H) from the American Type Culture Collection, H2452 tumour spheroids, and female BALB/c nu/nu mice inoculated intrathoracically with 5 x 10^6 H2452 cells
• Exposure: Adenoviral treatments: telomerase-specific oncolytic adenovirus OBP-301 (and GFP-expressing variant OBP-401), replication-defective heparanase-expressing adenovirus Ad-S/hep, and replication-deficient control dl312, at stated multiplicities of infection and plaque-forming unit doses; asbestos appears only as background
• Main results:
  • All four mesothelioma cell lines expressed CAR and detectable hTERT messenger RNA
  • OBP-301 killed all mesothelioma cell lines dose-dependently; multiplicity of infection of 10 caused lysis within 3 days
  • In mice, 1 x 10^8 PFU of OBP-301 reduced dissemination and total tumour nodule weight versus dl312 or saline, while 1 x 10^7 PFU had no apparent effect
  • Two injections of 1 x 10^8 PFU starting on day 1, 8, 22 or 29 gave statistically significant antitumour effects at day 43, but nodules were not completely eradicated
  • In H2452 spheroids, Ad-S/hep co-infection allowed OBP-401 GFP expression in deeper layers, whereas OBP-401 with dl312 gave surface-only signal
  • Combination of OBP-301 (1 x 10^8 PFU) plus Ad-S/hep (1 x 10^7 PFU) on days 8 and 15 reduced tumour weights at day 43 more than OBP-301 alone; Ad-S/hep alone did not affect tumour weights
  • Survival over 12 weeks: 1 of 7 (14.3%) mice given OBP-301 alone versus 5 of 7 (71.4%) given OBP-301 plus Ad-S/hep
• The authors' conclusion: The authors concluded that telomerase-specific oncolytic adenoviruses had therapeutic potential against human malignant pleural mesothelioma in vitro and in vivo, that adding heparanase-expressing adenovirus enhanced virus distribution and antitumour effects, and that phase II studies in mesothelioma patients are warranted
• Limitations the authors state:
  • Tumour weights rose as treatment was delayed and nodules were not completely eradicated, so the authors state additional approaches are needed
  • The authors note a risk that over-expression of extracellular-matrix-digesting enzymes such as heparanase could promote tumour metastasis
  • The authors state the most effective enzyme for promoting viral penetration into tumour masses has not been determined

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Prognosis, Mesothelioma, Intrathoracic, Malignant Mesothelioma.

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