HETEROGENEITY OF CHEMOSENSITIVITY IN 6 CLONAL CELL-LINES DERIVED FROMA SPONTANEOUS MURINE ASTROCYTOMA AND ITS RELATIONSHIP TO GENOTYPIC AND PHENOTYPIC CHARACTERISTICS

Heterogeneity in drug sensitivity must, in part, account for the relat ive lack of success with single agent chemotherapy for glioblastoma mu ltiforme (GEM). In order to develop in vitro model systems to investig ate this, clones derived from the VM spontaneous murine astrocytoma ha ve been characterised with regard to drug sensitivity. Six clonal cell lines have been tested for sensitivity to a panel of cytotoxic drugs using an intermediate duration S-35-methionine uptake assay. These lin es have previously been extensively characterised with regard to morph ological, antigenic, kinetic, tumourigenic potential in syngeneic anim als and chromosomal properties and display considerable heterogeneity. The present study indicates that heterogeneity extends to sensitivity to all classes of cytotoxic drugs. The greatest difference in sensiti vity between the clones was seen in response to cell cycle-specific dr ugs like the Vinca alkaloids (14-fold and 20-fold for vincristine (VCR ) and vindesine (VIND) respectively), while the nitrosoureas, CCNU and BCNU displayed a smaller fold difference in sensitivity (4.3 and 3.6- fold difference respectively). All the clones were considerably more r esistant to the adriamycin (ADM), cis-platinum (C-PLAT) and the Vinca alkaloids than the parental cell line although the difference in sensi tivity between the clones and parental cell line were less marked for the nitrosoureas and procarbazine (PCB). It has also been possible to examine the relationship between drug sensitivity and the phenotypic a nd genotypic properties of these clonal cell lines. There is a relatio nship between chromosome number and sensitivity of a wide variety of c ytotoxic drugs including the nitrosoureas, Vinca alkaloids, PCB, C-PLA T, BLEO but not ADR or 5-FU. Clones with small numbers of chromosomes were more resistant than clones with gross polyploidy. Similarly, sens itivity to Vinca alkaloids and ADM? but not other classes of drugs, wa s greatest in cells with numerous cytoplasmic processes and which did not express large amounts of cell surface fibronectin. Preliminary exp eriments have been conducted on reconstituting clonal mixtures of cell s with different sensitivity to Vinca alkaloids and results from these studies indicate that the drug resistance phenotype is dominant, with clonal mixtures of sensitive and resistant cell adopting the sensitiv ity of the more resistant partner. These cell lines should prove to be useful models for examining the cell biological basis of drug resista nce in glioma and may lead to the identification and exploitation of n ovel cellular targets in new therapies for GEM.