Treatment > Carmustine · Chemoresistance · Procarbazine

Meeting Abstract

Modulation of resistance to BCNU by depleting MGMT activity with procarbazine in patients with relapsed high-grade gliomas

Beith J.^1,2, Cook R.³, Robinson B.², Levi J.¹, Bell D.¹, Wheeler H.¹ 

Oncology^l, Molecular Genetics² & Neurosurgery ³ Departments, Royal North Shore Hospital, Sydney, Australia.

O⁶-methylguanine methyltransferase (MGMT) has been shown in vitro to be the major mechanism of resistance to chloroethylnitrosoureas (CNUs) and depletion of MGMT has been reported to enhance the cytotoxic effect of CNUs in human glioma cell lines.
We report an attempt to modulate resistance to BCNU in 21 patients with relapsed high grade gliomas.
Procarbazine 200 mg/m² was administered days 1-5 to deplete MGMT prior to BCNU 80 mg/m², which was given days 3-5.
Vincristine 1.4 mg/m² was given day 3.
To assess depletion of MGMT, MGMT activity was measured in peripheral blood monocytes (PBM) before and after 2 days treatment with procarbazine.
17 patients were assessable for response.
Using standard criteria, there were 2 (12%) CRs, 5 (29%) PRs and 5 (29%) with SD.
5 (29%) had progressive disease.
Median time to progression was 30 weeks and median overall survival 30 weeks.
These results are among the better results reported for chemotherapy in this disease.
Associated with the increased response rates was increased myelo, pulmonary and hepatic toxicity.
There was a mean decrease in MGMT activity, to 54% of pre-procarbazine level (p<0.001).
There was no significant correlation between percent decrease in MGMT and response.
We conclude that procarbazine decreases the MGMT activity in PBMs and this protocol is associated with higher than expected response rates and increased toxicity.

© Copyright 2002 American Society of Clinical Oncology. All rights reserved worldwide