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Relationship Between O6-methylguanine-DNA Methyltransferase Levels and Clinical Response Induced by Chloroethylnitrosourea Therapy in Glioma Patients

Published online by Cambridge University Press:  05 August 2019

Zhong-Ping Chen ,
Daniel Yarosh ,
Yesenia Garcia ,
Donatella Tampieri ,
Gérard Mohr ,
Areti Malapetsa ,
Adrian Langleben  and
Lawrence C. Panasci
Zhong-Ping Chen
Affiliation:
From Lady Davis Institute for Medical Research, the Sir Mortimer B. Davis Jewish General Hospital Division of Neurosurgery, the Sir Mortimer B. Davis Jewish General Hospital
Daniel Yarosh
Affiliation:
Applied Genetics Inc., New York, U.S.A.
Yesenia Garcia
Affiliation:
Applied Genetics Inc., New York, U.S.A.
Donatella Tampieri
Affiliation:
Montreal Neurological Institute, Montreal, Quebec
Gérard Mohr
Affiliation:
Division of Neurosurgery, the Sir Mortimer B. Davis Jewish General Hospital
Areti Malapetsa
Affiliation:
From Lady Davis Institute for Medical Research, the Sir Mortimer B. Davis Jewish General Hospital
Adrian Langleben
Affiliation:
Division of Medical Oncology, Royal Victoria Hospital, Montreal, Quebec
Lawrence C. Panasci*
Affiliation:
From Lady Davis Institute for Medical Research, the Sir Mortimer B. Davis Jewish General Hospital Division of Medical Oncology, the Sir Mortimer B. Davis Jewish General Hospital
*
Reprint requests to: Lawrence C. Panasci, the Lady Davis Institute for Medical Research, the Sir Mortimer B. Davis Jewish General Hospital, 3755 Côte Ste Catherine, Montreal, Quebec, Canada H3T 1E2
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Abstract:

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Background:

Adjuvant nitrosourea chemotherapy fails to prolong survival significantly as many tumors demonstrate resistance to these drugs. It has been documented in cell lines that O6-methylguanine DNA methyltransferase (MGMT) plays an important role in chloroethylnitrosourea (CENU) drug resistance.

Methods:

We evaluated MGMT expression in 22 glioma specimens by using an immunofluorescence assay and compared the results with clinical responses of the patients to CENU-based chemotherapy.

Results:

Eight tumor samples had no detectable MGMT, whereas other samples had from 9,989 to 982,401 molecules/nucleus. In one group (12 patients), the tumor decreased in size or was stable (effective group), whereas in the other group (10 patients), the tumor demonstrated continuous growth during chemotherapy (progressive group). The Mer- patients (MGMT < 60,000 molecules/nucleus) appeared to have more chance of stable disease or response to CENU therapy than the Mer+ patients (MGMT > 60,000 molecules/nucleus) (X2 = 4.791, p = 0.0286). In patients with glioblastomas multiforme (GBMs), the median time to progression (TTP) of Mer+ patient was shorter than that of Mer- patient (t = 2.04, p = 0.049). As a corollary, the MGMT levels were significantly higher in GBM tumors from the progressive group than those from the effective group (t = 2.26, p = 0.029). However, there was no significant correlation between MGMT levels and either the survival time (r = 0.04, p = 0.8595) or TTP (r = 0.107, p = 0.6444).

Conclusion:

This study suggests that being MGMT positive is indicative of a more aggressive disease that progresses more rapidly with CENU therapy. However, MGMT negative tumors are not always sensitive to CENU agents, suggesting that other factors are also important.

Résumé:

Résumé:Introduction:

La chimiothérapie adjuvante à base de nitrosurées ne prolonge pas significativement la survie des patients atteints de gliome malin parce que plusieurs de ces tumeurs y sont résistantes. Il a été démontré qu'en culture cellulaire, la o6-méthylguanine-ADN méthyltransférase (MGMT) joue un rôle important dans la résistance pharmacologique à la chloroéthyl-nitrosurée (CENU).

Méthodes:

Nous avons évalué l'expression de la MGMT dans 22 spécimens de gliome à l'aide d'un essai par immunofluorescence et avons comparé ces résultats avec la réponse clinique des malades traités par chimiothérapie à base de la CENU.

Résultats:

Huit spécimens n'avaient pas de MGMT détectable alors que les autres spécimens avaient de 9,989 à 982,401 molécules/noyau. Dans un groupe de 12 malades, la taille de la tumeur a diminué ou est restée stable (groupe répondeur), tandis que dans un autre groupe de 10 patients, la tumeur a continué de progresser durant la chimiothérapie (groupe avec progression). Le groupe de patients Mer- (MGMT < 60,000 molécules/noyau) a semblé avoir une plus grande probabilité que la maladie soit stable ou de présenter une réponse au traitement par la CENU que le groupe Mer+ (MGMT < 60,000 molécules/noyau) (X2 = 4.791, p = 0.0286). Chez les malades porteurs de glioblastomes multiformes (GBM), le laps de temps moyen écoulé jusqu'à ce qu'on note une progression (TMP) était plus court pour le groupe Mer+ que pour le groupe Mer- (t =2.04, p = 0.049). En corollaire, les niveaux de MGMT étaient significativement plus élevés dans les tumeurs des patients du groupe avec progression que dans celles des patients du groupe où le traitement était efficace (t = 2.26, p = 0.029). Cependant, il n'y avait pas de relation significative entre les niveaux de MGMT et le temps de survie (r = 0.04, p = 0.8595) ou le TMP (r = 0.107, p = 0.644).

Conclusion:

Cette étude suggère que la positivité pour la MGMT indique la présence d'une maladie plus agressive qui progresse plus rapidement sous traitement par la CENU. Cependant, les tumeurs négatives pour la MGMT ne sont pas toujours sensibles à la CENU, ce qui suggère que d'autres facteurs sont également importants dans la réponse à la chimiothérapie.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 26 , Issue 2 , May 1999 , pp. 104 - 109
Copyright
Copyright © The Canadian Journal of Neurological 1999

Footnotes

Presented as the Francis McNaughton Memorial Prize at the 33rd Meeting of the Canadian Congress of Neurological Sciences, June 19, 1998 in Montreal, Quebec.

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