Interferon (IFN)-alpha and IFN-gamma in combination with methotrexate: in vitro sensitivity studies in four human mesothelioma cell lines

Our plain-English summary of Interferon (IFN)-alpha and IFN-gamma in combination with methotrexate: in vitro sensitivity studies in four human mesothelioma cell lines, by A. Hand, K. Pelin, K. Mattson, et al (Anti-cancer Drugs, 1995).

The study

• Authors: A. Hand, K. Pelin, K. Mattson, K. Linnainmaa
• Journal: Anti-cancer Drugs
• Published: 1995;6(1):77-82
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mesothelioma is a malignant tumor of the serous surfaces in the thorax and abdomen, which has proved exceptionally resistant to treatment. A recent phase II trial of a high-dose methotrexate regime on 63 Norwegian patients has, however, achieved a response rate of 37%. Some responses have also been achieved using interferon (IFN)-gamma administered intrapleurally or recombinant (r) IFN-alpha administered subcutaneously. Our earlier in vitro sensitivity studies of mesothelioma cell lines showed that IFN augments the response to chemotherapeutic agents in mesothelioma. The aim of this study was to assess the response of four mesothelioma cell lines, derived from diffuse asbestos-related pleural malignant mesothelioma, to methotrexate alone and in combination with recombinant IFN-alpha and IFN-gamma. Anti-proliferative effects were assayed by vital dye exclusion. A combination of IFN-alpha and IFN-gamma consistently augmented the response of the cell lines to methotrexate, by as much as 75% for one cell line, although the response to the individual IFNs was variable. We were also able to compare the effects of natural IFN-beta with those of IFN-alpha and IFN-gamma. The IFN-beta sensitivity profile for each of the four cell lines was similar to that of IFN-alpha. In two cell lines, the combination of IFN-beta and IFN-gamma produced a similar effect to the IFN-alpha and IFN-gamma combination.

In plain English

This laboratory study used cancer cells, not patients or asbestos exposure. Finnish researchers tested four human mesothelioma cell lines from diffuse asbestos-related pleural malignant mesothelioma against the drug methotrexate. They tested it alone and with recombinant interferon-alpha, interferon-gamma, or both; they also tested natural interferon-beta. Surviving cells were counted after 48 hours of treatment. All four lines were similarly sensitive to methotrexate alone. Of the methotrexate treatments, all four were most sensitive to methotrexate plus both interferons, which the authors reported augmented the response by as much as 75% for one cell line. Responses to methotrexate with a single interferon varied. Only one cell line, M33K, showed a clear interaction between methotrexate and the interferon combination; in M38K, no methotrexate-interferon combination appeared to reduce growth as much as the two interferons alone. Responses to interferon-beta resembled those to interferon-alpha. The authors concluded that their results support continued searching for a role for interferon in treating malignant mesothelioma. They urged caution because methotrexate acts indirectly on DNA, through the folate pool, and the dynamics of this interaction were not yet understood.

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) drug-sensitivity experiments on human mesothelioma cell lines
• Who was studied: Four human mesothelioma cell lines (M9K, M14K, M33K, M38K), established by the authors' group in Helsinki, Finland, from diffuse asbestos-related pleural malignant mesothelioma. Three (M9K, M33K, M38K) came from tumors of mixed histology and one (M14K) came from an epithelial-type tumor. Three came from the primary tumors of previously untreated patients. M9K came from the metastatic tumor of a patient previously treated with mitoxantrone and radiotherapy.
• Exposure: No asbestos exposure was studied. The cells were exposed for 48 hours to methotrexate alone and to methotrexate combined with recombinant IFN-alpha, recombinant IFN-gamma, or both. The IFN was added at a fixed 0.01 micrograms per ml. Natural IFN-beta was also tested, with and without IFN-gamma. Mitoxantrone was compared with methotrexate in two cell lines.
• Main results:
  • The four cell lines had very similar sensitivities to methotrexate alone.
  • Among the methotrexate conditions tested, all four cell lines were most sensitive to methotrexate plus the IFN-alpha and IFN-gamma combination. The authors state that this augmented the response to methotrexate by as much as 75% for one cell line.
  • Responses to methotrexate with a single interferon varied. M9K responded to methotrexate with either IFN. M14K responded to neither. M33K responded to methotrexate with IFN-gamma but not with IFN-alpha.
  • Against the growth reduction expected from the IFN combination alone, a noticeable interaction between methotrexate and the IFN combination was seen in only one cell line, M33K. In M9K and M14K there was barely any further reduction in viable cells.
  • In M38K, no combination of methotrexate with IFN appeared to reduce growth as much as the IFN combination alone.
  • In all four cell lines, the response to natural IFN-beta was similar to the response to IFN-alpha.
  • In the two cell lines tested with it (M9K and M38K), IFN-beta plus IFN-gamma had an effect very similar to that of IFN-alpha plus IFN-gamma.
  • In the two cell lines compared, both were marginally more sensitive to mitoxantrone than to methotrexate, with and without the IFN combination.
• The authors' conclusion: The authors concluded that methotrexate activity appears to be potentiated by IFN in vitro. They also concluded that their results support the continued search for a role for IFN in treating malignant mesothelioma, and that cell line studies should be encouraged to screen new agents and combinations.
• Limitations the authors state:
  • The authors state that the results should be interpreted with caution. Methotrexate acts indirectly on DNA via the cellular folate pool, and the dynamics of this interaction are not yet understood.
  • The authors note that the features distinguishing cell line M33K do not explain why it was more sensitive to methotrexate plus IFN.

Topics

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

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

Related studies

• Interferon-alpha and -gamma in combination with chemotherapeutic drugs: in vitro sensitivity studies in four human mesothelioma cell lines — A.M. Hand, K. Husgafvel-Pursiainen, et al. (1992)
• In vitro effects of recombinant human interferon gamma on human mesothelioma cell lines — L. Zeng, A. Buard, et al. (1993)
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• Effects of natural interferon alpha, natural tumor necrosis factor alpha and their combination on human mesothelioma xenografts in nude mice — T. Ohnuma, L. Szrajer, et al. (1993)
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• Safety, feasibility and therapeutic activity of intrapleural autologous lymphocyte conditioned medium followed by systemic recombinant interleukin-2 and interferon-alpha in a patient with malignant pleural mesothelioma — S. Duensing, H. Hamm, et al. (1997)

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