Relationship between ornithine decarboxylase levels in anaplastic gliomas and progression-free survival in patients treated with DFMO-PCV chemotherapy.
The purpose of this study was to assess the relationship between progression-free survival (PFS) in patients treated with DFMO + PCV (procarbazine, CCNU, vincristine) chemotherapy for malignant gliomas with tumor cell ornithine decarboxylase (ODC) activity. Formalin-fixed slides were obtained for study patients with anaplastic gliomas (AGs) and glioblastoma treated on protocol DM92-035. ODC levels were measured using an antibody to ODC coupled to Alexa 647 dye (Ab-ODC-Alexa 647). Ab-ODC-Alexa 647 intensity in transgenic murine hearts of differing ODC activity was used to calculate ODC activity in tumor cell nucleoplasm. In total, tumor specimens for 31 of 114 (27%) patients treated on the AG strata and 10 patients from the GBM strata were obtained. We found that tumor ODC level heterogeneity increased with increasing tumor malignancy. In a Cox proportional hazards model, PFS was found to be inversely related to median tumor ODC activity, with an unadjusted hazard ratio for median ODC group (>3.3 vs. </=3.3 nmol/30 min/mug protein) of 5.8 (p < 0.0001); a median PFS of 522 weeks for patients with AGs with median ODC activity </= 3.3 and 31 weeks for the 8 AG and 10 glioblastoma patients with ODC activity > 3.3 nmol/30 min/mug protein. Of AG tumors in which ODC activity was evaluated, 26% had ODC levels > 3.3 nmol/30 min/mug protein. This study shows that Ab-ODC-Alexa 647 fluorescence intensity can be used as a surrogate marker of ODC biochemical activity in AGs and can predict PFS to DFMO-based chemotherapy.
Levin
Victor A
VA
Department of Neuro-Oncology and M. D. Anderson Clinical Oncology Program, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. vlevin@mdanderson.org
Jochec
Jacob L
JL
Shantz
Lisa M
LM
Aldape
Kenneth D
KD
D000708:Anaplasia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D018450:Disease Progression; D000518:Eflornithine / Q000627:therapeutic use*; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D015996:Survival Rate; D014751:Vindesine / Q000627:therapeutic use
D003520:Cyclophosphamide; D009955:Ornithine Decarboxylase; D002945:Cisplatin; D014751:Vindesine; D000518:Eflornithine