Complete regression of human malignant mesothelioma xenografts following local injection of midkine promoter-driven oncolytic adenovirus

Our plain-English summary of Complete regression of human malignant mesothelioma xenografts following local injection of midkine promoter-driven oncolytic adenovirus, by S. Kubo, Y. Kawasaki, N. Yamaoka, et al (The Journal of Gene Medicine, 2010).

The study

• Authors: S. Kubo, Y. Kawasaki, N. Yamaoka, M. Tagawa, N. Kasahara, N. Terada, H. Okamura
• Journal: The Journal of Gene Medicine
• Published: 2010;12(8):681-92
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma is a highly aggressive tumor with poor prognosis. We hypothesized that the tumor-specific midkine (Mdk) promoter could confer transcriptional targeting to oncolytic adenoviruses for effective treatment of malignant mesothelioma.

Methods: We analysed Mdk expression by quantitative reverse transcription-polymerase chain reaction in six human mesothelioma cell lines, and tested Mdk promoter activity by luciferase reporter assay. On the basis of these data, we constructed a replication-selective oncolytic adenovirus designated AdMdk-E1-iresTK. This virus contains a Mdk promoter-driven adenoviral E1 gene and herpes simplex virus-thymidine kinase (TK) suicide gene and cytomagalovirus promoter-driven enhanced green fluorescent protein marker gene. Selectivity of viral replication and cytolysis were characterized in normal versus mesothelioma cells in vitro, and intratumoral spread and antitumor efficacy were investigated in vivo.

Results: Mdk promoter activity was restricted in normal cells, but highly activated in mesothelioma cell lines. AdMdk-E1-iresTK was seen to efficiently replicate, produce viral progeny and spread in multiple mesothelioma cell lines. Lytic spread of AdMdk-E1-iresTK mediated the efficient killing of these mesothelioma cells, and its in vitro cytocidal effect was significantly enhanced by treatment with the prodrug, ganciclovir. Intratumoral injection of AdMdk-E1-iresTK caused complete regression of MESO4 and MSTO human mesothelioma xenografts in athymic mice. In vivo fluorescence imaging demonstrated intratumoral spread of AdMdk-E1-iresTK-derived signals, which vanished after tumor eradication.

Conclusions: These data indicate that transcriptional targeting of viral replication by the Mdk promoter represents a promising general strategy for oncolytic virotherapy of cancers with up-regulated Mdk expression, including malignant mesothelioma.

Copyright 2010 John Wiley & Sons, Ltd.

In plain English

This laboratory and animal study tested whether the midkine (Mdk) gene promoter could restrict replication of an oncolytic adenovirus to human malignant mesothelioma cells. The authors measured Mdk and CAR mRNA in six human mesothelioma cell lines plus normal mesothelial cells, and built four adenoviruses, including Ad881 (Mdk promoter driving adenoviral E1 linked to a herpes simplex virus thymidine kinase suicide gene). Mdk was expressed in all six mesothelioma lines but was low in normal mesothelial cells; MESO4 and MSTO showed the highest expression (more than 100-fold above normal mesothelial cells). Ad881 produced 2.6-, 51.3- and 21.2-fold more viral progeny than the CMV-driven Ad883 in MESO1, MESO4 and MSTO cells. In athymic nude mice, a single intratumoral injection of Ad881 on day 0 caused complete regression of MESO4 xenografts without ganciclovir, while MSTO xenografts injected on days 0 and 6 regressed completely only when ganciclovir was also given. After intravenous injection, serum ALT was 225.5 plus or minus 39.52 U/l with Ad883 versus 29.70 plus or minus 14.98 U/l with Ad881. Asbestos was mentioned only as background on mesothelioma causation.

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 (in vitro cell culture) and animal xenograft experiment constructing and testing a midkine promoter-driven oncolytic adenovirus
• Who was studied: Six human malignant mesothelioma cell lines (MESO1, MESO4, H28, H2052, H2452, MSTO), normal human mesothelial cells, smooth muscle cells, fibroblasts, Met5A and 293/293T cells; and 6-7-week-old female BALB/c-nu/nu (nude) mice bearing subcutaneous MESO4 or MSTO xenografts (group sizes of 3, 4 or 8)
• Exposure: Infection with recombinant adenoviruses: Ad881 (Mdk promoter-driven E1 plus HSV-TK), Ad883 (CMV-driven E1 plus HSV-TK), Ad884 (Mdk-driven HSV-TK, replication-defective), Ad885 (CMV-driven HSV-TK), at MOIs 0.01-1000 in vitro and 5 x 10^8 TU intratumorally in vivo, with or without the prodrug ganciclovir
• Main results:
  • Mdk mRNA was found in all six mesothelioma cell lines, low in normal mesothelial cells and undetectable in smooth muscle cells; MESO4 and MSTO had the highest expression, more than 100-fold above normal mesothelial cells
  • Viral progeny production: Ad881 gave 2.6-, 51.3- and 21.2-fold higher production than Ad883 in MESO1, MESO4 and MSTO cells
  • In normal mesothelial cells and Met5A cells, Ad881 produced 3-4-fold less virus than Ad883
  • In MESO4 xenografts (single injection on day 0), Ad881 without ganciclovir caused complete regression, tumors barely palpable by 3 weeks post-infection
  • In MESO4 xenografts, the replication-defective Ad884 gave partial regression (40.9% reduction in tumor volume) only with ganciclovir, followed by regrowth
  • In MESO4 xenografts, Ad881 given with ganciclovir produced a 64.2% reduction in tumor volume by day 20, with regrowth thereafter
  • In MSTO xenografts, Ad884 with ganciclovir gave partial regression (23.2% reduction in tumor volume) followed by regrowth
  • In MSTO xenografts injected on days 0 and 6, Ad881 with ganciclovir (days 24-48) gave complete regression, with no regrowth up to 4 weeks after ganciclovir was discontinued; without ganciclovir Ad881 inhibited growth but did not eradicate the tumors
  • In a separate MSTO experiment with ganciclovir from days 14-28, tumor growth inhibition was 95.9% for Ad881, 73.7% for Ad883 and 44.6% for Ad884
  • After intravenous injection, serum ALT was higher with Ad883 (225.5 plus or minus 39.52 U/l) than with Ad881 (29.70 plus or minus 14.98 U/l), p = 0.0098
  • Serum ALT did not differ significantly between Ad881-injected mice (29.70 plus or minus 14.98 U/l) and the PBS control group (15.43 plus or minus 1.981 U/l), p = 0.3986
• The authors' conclusion: The authors concluded that the Mdk promoter is a tumor-specific regulatory element useful for targeting oncolytic adenovirus to malignant mesothelioma and that, because Mdk is up-regulated in many cancers, this may be a promising general strategy for transcriptionally targeted oncolytic virotherapy
• Limitations the authors state:
  • The authors noted that in MSTO cells, which have high Mdk but low CAR expression, the oncolytic effects were subtherapeutic compared with MESO4 cells
  • The authors noted that in the MESO4 xenograft model, ganciclovir treatment reduced the antitumoral efficacy achieved by oncolytic virotherapy alone
  • The authors stated it was difficult to compare their results directly with the two prior studies of transcriptionally targeted oncolytic adenovirus in mesothelioma, because of different cell line panels and absent CMV-driven controls

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Prognosis, Mesothelioma.

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