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DNA
mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response
to Temodal in newly diagnosed malignant glioma
Friedman
HS, McLendon RE, Kerby T, Dugan M, Bigner SH, Henry AJ, Ashley DM, Krischer J,
Lovell S, Rasheed K, Marchev F, Seman AJ, Cokgor I, Rich J, Stewart E, Colvin
OM, Provenzale JM, Bigner DD, Haglund MM, Friedman AH, Modrich PL
Department
of Surgery, Howard Hughes Medical Institute, Duke University Medical Center,
Durham, NC 27710, USA. fried003@mc.duke.edu
Purpose.
We evaluated the response to Temodal (Schering-Plough Research Institute,
Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as
the predictive value of quantifying tumor DNA mismatch repair activity and
O6-alkylguanine-DNA alkyltransferase (AGT).
Patients
and Methods. Thirty-three patients with newly diagnosed glioblastoma multiforme
(GBM) and five patients with newly diagnosed anaplastic astrocytoma (AA) were
treated with Temodal at a starting dose of 200 mg/m2 daily for 5 consecutive
days with repeat dosing every 28 days after the first daily dose.
Immunochemistry for the detection of the human DNA mismatch repair proteins MSH2
and MLH1 and the DNA repair protein AGT was performed with monoclonal antibodies
and characterized with respect to percent positive staining.
Results.
Of the 33 patients with GBM, complete responses (CRs) occurred in three
patients, partial responses (PRs) occurred in 14 patients, stable disease (SD)
was seen in four patients, and 12 patients developed progressive disease (PD).
Toxicity included infrequent grades 3 and 4 myelosuppression, constipation,
nausea, and headache.
Thirty tumors showed greater than 60% cells that stained for MSH2 and MLH1, with
three CRs, 12 PRs, three SDs, and 12 PDs.
Eight tumors showed 60% or less cells that stained with antibodies to MSH2
and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs.
Eleven tumors showed 20% or greater cells that stained with an antibody to AGT,
with 1 PR, 2 SDs, and 8 PDs.
Twenty-five tumors showed less than 20% cells that stained for AGT, with 3 CRs,
12 PRs, 4 SDs, and 6 PDs.
Conclusion.
These results suggest that Temodal has activity against newly diagnosed GBM and
AA and warrants continued evaluation of this agent. Furthermore, pretherapy
analysis of tumor DNA mismatch repair and, particularly, AGT protein expression
may identify patients in whom tumors are resistant to Temodal.
PMID:
9850030 [PubMed - indexed for MEDLINE]
Source:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9850030&dopt=Abstract
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