Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy

Our plain-English summary of Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy, by W.R. Smythe, H.C. Hwang, A.A. Elshami, et al (The Journal of Thoracic and Cardiovascular Surgery, 1995).

The study

• Authors: W.R. Smythe, H.C. Hwang, A.A. Elshami, K.M. Amin, S.M. Albelda, L.R. Kaiser
• Journal: The Journal of Thoracic and Cardiovascular Surgery
• Published: 1995;109(4):626-30; discussion 630-1
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma may prove to be an attractive candidate for somatic gene therapy with replication-deficient recombinant adenovirus transfer of a toxic, or drug sensitization gene. Transfer of the herpes simplex thymidine kinase type I gene (HSVtk), followed by exposure to the acyclic nucleoside drug ganciclovir, has been shown to be an effective tumor cell killing system. To study generalized applicability, we tested a number of thoracic malignant cell lines for their sensitivity to gancyclovir after infection with an adenoviral vector containing the HSVtk gene (Ad.RSVtk). Using the concentration of gancyclovir required to kill 50% of the cells (IC50) as a measure of sensitivity, we detected variable sensitivity among cell lines, with mesothelioma most sensitive (IC50 = 0.075 to 2.8 mumol/L gancyclovir), and non-small-cell carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 100 mumol/L). In contrast, an ovarian carcinoma line was extremely resistant (IC50 > 2000 mumol/L). To study the possible mechanisms for these differences, we studied cell lines with regard to their ability to be infected with an adenoviral vector containing a marker gene (Ad.CMVlacZ) and expression of the vitronectin receptor alpha v (an integrin cell adhesion molecule shown to be required for adenovirus internalization after initial binding). We found that the degree of lacZ transduction correlated with HSVtk sensitivity, whereas vitronectin receptor expression did not, suggesting that differences in initial viral binding ability, rather than internalization, may explain the sensitivity differences seen in vitro.

In plain English

This was a laboratory study of cancer cells grown in dishes, not of patients, and it did not examine asbestos exposure. The authors tested an experimental gene therapy: a disabled adenovirus carrying a herpes virus gene (HSVtk) that makes infected cells vulnerable to the drug ganciclovir. They tested three human mesothelioma cell lines, five human non-small-cell lung cancer lines, one normal human mesothelial line, one ovarian cancer line and one rat mesothelioma line. The ganciclovir dose needed to kill half the cells was below 3 micromoles per liter for every human mesothelioma line. It ranged from 1.0 to 100 for the lung cancer lines, was 25 for the normal mesothelial line, and was above 2000 for the ovarian line. The proportion of cells expressing a marker gene delivered by a second virus tracked their sensitivity. Levels of a cell-surface protein, alpha v integrin, did not. The authors concluded that sensitivity varied widely and that resistance appeared related to viral uptake, internalization or expression. They noted that how these results relate to tumors in the body remains to be determined.

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: In vitro laboratory experiment on cultured cell lines
• Who was studied: Cell lines, not people: three human malignant mesothelioma lines (1-45, REN, HeMe-B), five human non-small-cell carcinoma lines (Calu-6, SK-MES-1, H460, A549, H1264), one normal human mesothelial line (HPM), one human ovarian carcinoma line (Ovcar-5) and one Fisher rat malignant mesothelioma line (II-45); work at the University of Pennsylvania Medical Center, presented April 1994
• Exposure: No asbestos exposure was studied. Cells were infected with a replication-deficient adenovirus carrying the herpes simplex thymidine kinase gene (Ad.RSVtk) at 100 viral particles per cell, then exposed to ganciclovir at 0 to 2000 micromoles per liter. A second adenovirus carrying a marker gene (Ad.CMVlacZ) was also used.
• Main results:
  • All human mesothelioma lines had a ganciclovir IC50 (dose killing 50% of cells) below 3 micromoles per liter. In Table I these were 1-45: 0.075, REN: 1.5 and HeMe B: 2.8.
  • The IC50 of the non-small-cell carcinoma lines was generally higher, varying from 1.0 to 100 micromoles per liter.
  • The normal human mesothelial line (HPM, IC50 25) required roughly tenfold more ganciclovir than the least sensitive mesothelioma line. The ovarian carcinoma line Ovcar-5 was extremely insensitive (IC50 greater than 2000 micromoles per liter).
  • The amount of alpha v integrin on the cells varied and did not correlate with sensitivity to HSVtk/ganciclovir or with lacZ expression.
  • The percentage of cells expressing the lacZ marker gene delivered by the second virus was inversely correlated with the IC50, meaning lines with a higher percentage of marker-expressing cells were more sensitive. Mesothelioma lines tended to show a higher percentage of lacZ-positive cells. Fitted line slopes were 13.7 and -12.8.
• The authors' conclusion: The authors concluded that sensitivity to HSVtk/ganciclovir varies over a wide range. In their view, mesothelioma and non-small-cell lung cancer lines were quite sensitive and at least one ovarian carcinoma line was extremely resistant. They judged that the unknown resistance mechanism appears related to viral uptake, internalization or expression rather than resistance to the HSVtk enzyme.
• Limitations the authors state:
  • The relationship between cell sensitivity to ganciclovir in the laboratory and in the body remains to be determined.
  • More work is needed to determine which step in the viral cycle is blocked in resistant cells.

Topics

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

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

Related studies

• Use of protamine to augment adenovirus-mediated cancer gene therapy — M. Lanuti, C.E. Kouri, et al. (1999)
• Gene therapy using adenovirus carrying the herpes simplex-thymidine kinase gene to treat in vivo models of human malignant mesothelioma and lung cancer — H.C. Hwang, W.R. Smythe, et al. (1995)
• Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy — X.B. Deng, L. Xiao, et al. (2015)
• Efficacy of repeated adenoviral suicide gene therapy in a localized murine tumor model — E.S. Lambright, S.D. Force, et al. (2000)
• Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms — Z.G. Fridlender, J. Sun, et al. (2010)
• Adenovirus-mediated wild-type p53 overexpression reverts tumourigenicity of human mesothelioma cells — M. Giuliano, A. Catalano, et al. (2000)

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