Background: Although some patients with malignant gliomas respond to treatment with chemotherapeutic agents like BCNU, tumor recurrence inevitably occurs, heralding the development of chemoresistance. Treating and/or preventing chemoresistance requires distinguishing newly developed resistance from the presence of intrinsically resistant cells in the primary tumor population. This study relates the chromosomal complements of freshly resected astrocytomas to the cells' chemosensitivity and ultimately to the patients' response to treatment.
Methods: The authors dissociated 31 freshly resected human gliomas (5 astrocytomas, 10 anaplastic astrocytomas, 16 glioblastomas multiforme) into single cells, and performed cytogenetic analysis and BCNU sensitivity testing using the colony-forming assay (CFA) on first division cells from these tumors.
Results: The major cytogenetic abnormalities involved the loss of a sex chromosome in all three classes of gliomas and the gain of chromosome 7 in anaplastic astrocytoma and glioblastoma multiforme; clonal marker chromosomes were observed in only anaplastic astrocytoma and glioblastoma multiforme with no common rearrangement observed among the tumors. The five astrocytomas were near-diploid (2n+/-, 35-57 chromosomes/cell), and all were resistant to BCNU. Seven of ten anaplastic astrocytomas were composed primarily of 2n+/- cells and were BCNU resistant. Three other anaplastic astrocytomas had a 39% or greater representation of 4n+/- cells (88-101 chromosomes/cell), and these tumors were sensitive to BCNU. Ten of 16 glioblastomas multiforme were composed predominantly of 2n+/- cells and were resistant to carmustine. Six other glioblastomas multiforme had at least 41% 3n+/- (58-87 chromosomes/metaphase) and 4n+/- cell populations and were sensitive to carmustine. Thus, gliomas demonstrating BCNU sensitivity were more than 60% hyperdiploid (60 or more chromosomes/metaphase) with 1 to 8 clonal marker chromosomes and multiple clonal populations involving complex karyotypic deviations. In contrast, all 22 resistant tumors were composed primarily of near-diploid cells. Only 4 of 22 tumors had a clonal marker, and the chromosome ploidy changes were less extensive.
Conclusions: In freshly resected untreated human gliomas, BCNU is most effective against hyperdiploid cells that have extensive ploidy changes and chromosome rearrangement, whereas resistance to carmustine is characteristic of near-diploid populations with few ploidy changes and rearranged chromosomes. This observation was consistent for all three classes of gliomas.