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Ann Thorac Surg 2000;70:936
© 2000 The Society of Thoracic Surgeons
Discussion
DR CAROLYN E. REED (Charleston, SC): Doctor Jones has presented a series of elegant studies that focus on a tremendously important subject, which is chemoresistance of non–small cell lung cancer. He is to be commended for this work. I would like to thank Dr Jones for sending me the manuscript in advance.
I have several questions for you, Dr Jones. If I am correct, nuclear factor-kappa B (NF-
B) upregulates a number of apoptosis inhibitors. Can you give us some insight into whether these inhibitors share a common mechanism of upregulation by NF-B?
Two, how are you going to progress to in vivo experiments?
Three, is there any evidence that different histologic types of non–small cell lung cancer have differing levels of NF-B?
Finally, what substance would you plan to use in vivo to target NF-B?
I enjoyed your paper and I wish to thank you again for sending me the manuscript in advance and I look forward to further reports from your laboratory.
DR JONES: There are several known NF-B-regulated gene products, which inhibit apoptosis. Two specific products are members of the inhibitors of apoptosis protein families, CIAP-1 and CIAP-2. Certainly with CIAP-2, if NF-B is blocked, there is inhibition of both basal and inducible levels of CIAP-2. Another NF-B regulated gene product that is clearly involved in apoptosis is A1, which is a Bcl-2 homologue. This is transcriptionally regulated by NF-B and is another downstream NF-B target which provides the cell with an anti-apoptotic function.
Future in vivo studies are currently getting underway in the lab. Two different xenografting strategies will be employed. First we will take the transformed non-small-cell lung cancer cell lines that we have looked at here, inject them into athymic node mice, and then perform adenoviral-mediated delivery of the super-repressor of NF-B and measure the tumor growth characteristics. The second xenograft model, (which perhaps more closely resembles the clinical situation), will utilize human non-small-cell lung cancers and intratracheally instill them into athymic node mice.
With respect to the third question, I don’t know of any data that different histologic subtypes have differing levels of NF-B. There is a paper from M.D. Anderson published in Cancer Research in 1995 which showed that 9 of 11 fresh human non-small-cell lung cancers had elevated expression levels of p50, which is one of the subunits of NF-B. So I do think that NF-B is likely to have basal expression in most human lung cancers, but I don’t know that this has been stratified depending on the histologic subtype.
Finally, the strategies we would use in vivo to inhibit NF-B are limited. There are several protease inhibitors that could be used, such as Tosylphenylalanyl chloromethyl ketone (TPCK), and others. The problem with those agents is that they also inhibit other transcription factors, including CREB and AP-1. Another way to inhibit NF-B in vivo is, as I mentioned, adenoviral-mediated delivery of the dominant-negative NF-B gene. There are also small molecule inhibitors and peptide aldehyde inhibitors, such as PS-341 and MG-132, which will also block NF-B activation.
DR THOMAS M. EGAN (Chapel Hill, NC): Doctor Jones, that was a very nice presentation. We will miss you back home.
I have a question for you about the effect of your inhibitor on apoptosis without the chemotherapeutic agent, in other words, affecting the cell line. Does that in and of itself accelerate apoptosis?
DR JONES: The answer is no. If you perform a stable transfection with the super-repressor, there is no cell growth inhibition. In addition, these cells are not sensitized to undergo apoptosis without treating them with an inducer of apoptosis.
DR EGAN: Are you aware of any pharmacologic methods that might be used to interfere with NF-B dissociation, and accomplish the same thing without the vector?
DR JONES: There are an increasing number of pharmaceutical agents being evaluated. PS-341 is a small molecule inhibitor currently being evaluated. There are also antioxidants, which are also involved in downregulating NF-B.
DR DAO M. NGUYEN (Bethesda, MD): I really enjoyed your talk. I have two questions. One, does this strategy also sensitize normal cells to the chemotherapeutic agent? Two, have you observed the same phenomenon with other chemotherapeutic agents, such as cisplatin, Taxol, and so on?
Thank you.
DR JONES: To answer your first question, I do not know because I have not looked in normal human tissue whether inhibition of NF-B would sensitize those cells to undergo apoptosis as well. That is a good question.
With respect to your second question regarding other chemotherapeutic agents, I have looked at CPT-11 and cisplatin. Both of these agents induce NF-B in these cell lines, although cisplatin does not induce nearly as strong as CPT-11. Other studies have looked at colorectal carcinoma cells, fibrosacoma cell lines, and other different chemotherapeutic agents, including Taxol, etoposide, and Adriamycin. All agents have been shown to activate NF-B in those cell lines. So I think the chemotherapy-induced NF-B activation is not cell-type-specific and in our hands it’s not chemotherapeutic agent-specific
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Ann. Thorac. Surg. 2000 70: 930-936.
Ann. Thorac. Surg. 2000 70: 937.
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