gms | German Medical Science

Objective: The disparate prognosis between different astrocytic tumors cannot be adequately accounted for by the classical clinical variables, and resistance to chemotherapeutic drugs is a major cause of treatment failure. The identification of drug metabolizing enzymes within the human blood-brain-barrier raises the question whether these enzymes act in concert with the ABC transporters to effect the distribution of drugs. We set to identify the association between expression profile and characteristics such as tumor grade, pathology, origin, chemotherapy in a total of six drug-metabolizing and drug-resistance genes.

Method: Using real-time quantitative RT-PCR, we quantified the expression of three drug-metabolizing genes (ALDH1A1, CYP1B1and GSTP1) and three drug-resistance genes (ABCB1, ABCC1 and ABCG2) in a set of 71 astrocytic tumor samples. We examined the differences between the three degrees of malignancy (grade II-IV), primary and recurrent gliomas, pure and mixed astrocytic tumors, with and without chemotherapy. We also studied whether the expression profile changes as the same tumor progresses. Results are reported as ΔCt between the marker and reference gene mRNA levels. Level of significance was set at 0.05.

Results: For all genes -except GSTP1- the higher the tumor grade, the weaker the mRNA expression was. For ALDH1A1, CYP1B1 and ABCC1 this difference between low-grade and high-grade tumors was statistically highly significant (ALDH1A1: M_LG=10,24 vs M_HG=4,32, CYP1B1: M_LG=3,66 vs M_HG=1,41 and ABCC1: M_LG=4,19 vs M_HG=2,62 p<0,009). Neither chemotherapy treatment nor the mixed oligoastrocytoma subtype seems to play a role in the expression of any of the studied genes. Recurrent glioblastomas tend to preserve the expression levels they had during initial diagnosis. For 11 patients, we had samples from the three grades of tumor progression: For ALDH1A1 and CYP1B1 we found that the transcriptional product diminishes as the tumor grade progresses (p=0,016).

Conclusions: Our data show that the mRNA expression of ALDH1A, CYP1B1 and ABCC1 might play a role in the drug resistance mechanisms of glioblastomas. For ALDH1A and CYP1B1 the degree of expression is also affected by tumor progression into malignancy in individual patients.