CHROMOSOME-NUMBER AND CARMUSTINE SENSITIVITY IN HUMAN GLIOMAS

Background. Although some patients with malignant gliomas respond to t reatment with chemotherapeutic agents like BCNU, tumor recurrence inev itably occurs, heralding the development of chemoresistance. Treating and/or preventing chemoresistance requires distinguishing newly develo ped resistance from the presence of intrinsically resistant cells in t he primary tumor population. This study relates the chromosomal comple ments of freshly resected astrocytomas to the cells' chemosensitivity and ultimately to the patients' response to treatment. Methods. The au thors dissociated 31 freshly resected human gliomas (5 astrocytomas, 1 0 anaplastic astrocytomas, 16 glioblastomas multiforme) into single ce lls, and performed cytogenetic analysis and BCNU sensitivity testing u sing the colony-forming assay (CFA) on first division cells from these tumors. Results. The major cytogenetic abnormalities involved the los s of a sex chromosome in all three classes of gliomas and the gain of chromosome 7 in anaplastic astrocytoma and glioblastoma multiforme; cl onal marker chromosomes were observed in only anaplastic astrocytoma a nd glioblastoma multiforme with no common rearrangement observed among the tumors. The five astrocytomas were near-diploid (2n+/-, 35-57 chr omosomes/cell), and all were resistant to BCNU. Seven of ten anaplasti c astrocytomas were composed primarily of 2n+/- cells and were BCNU re sistant. Three other anaplastic astrocytomas had a 39% or greater repr esentation of 4n+/- cells (88-101 chromosomes/cell), and these tumors were sensitive to BCNU. Ten of 16 glioblastomas multiforme were compos ed predominantly of 2n+/- cells and were resistant to carmustine. Six other glioblastomas multiforme had at least 41% 3n+/- (58-87 chromosom es/metaphase) and 4n+/-cell populations and were sensitive to carmusti ne. Thus, gliomas demonstrating BCNU sensitivity were more than 60% hy perdiploid (60 or more chromosomes/metaphase) with 1 to 8 clonal marke r chromosomes and multiple clonal populations involving complex karyot ypic deviations. In contrast, all 22 resistant tumors were composed pr imarily 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 ag ainst hyperdiploid cells that have extensive ploidy changes and chromo some rearrangement, whereas resistance to carmustine is characteristic of near-diploid populations with few ploidy changes and rearranged ch romosomes. This observation was consistent for all three classes of gl iomas.