Differential drug sensitivity of human neuroblastoma cells

A 6-day in vitro growth-inhibition assay was used to determine relative sensitivity of six human neuroblastoma cell lines to three classes of cancer chemotherapeutic agents: antimetabolites (methotrexate, methasquin, and cytarabine); antimitotics (vincristine, vinblastine, vindesine, colchicine, and demecolcine); and antibiotics (dactinomycin and doxorubicin). Human fibroblast lines served as a reference standard. Whereas response to antimetabolites by four of five neuroblastoma lines tested was similar to that of fibroblasts, SK-N-MC cells were significantly more sensitive (fivefold to 16-fold) to the three drugs. Human neuroblastoma cell lines were also differentially sensitive to antimitotics, especially to vincristine. In particular, SK-N-MC, IMR-32, and LA-N-2 cells were threefold to 17-fold more sensitive to this drug than were the SK-N-SH and SK-N-BE(2) lines. With the exception of SK-N-SH, all of the human neuroblastoma lines were considerably more sensitive to vincristine than were human fibroblasts. The same three highly vincristine-responsive lines were also significantly more sensitive to the other alkaloidal drugs as compared to fibroblasts. However, human neuroblastoma and fibroblastic cells responded similarly to the two antibiotics. The only cellular attribute consistently correlated with greater sensitivity to the antimitotics among the six cell lines tested was expression of the neurotransmitter biosynthetic enzyme choline acetyltransferase. A differential response to the vinca alkaloids was also exhibited by clonal sublines of SK-N-SH. One subpopulation (SH-EP) expressing a nonneuronal, substrate-adherent, variant phenotype was at least fourfold to eightfold more drug sensitive than its neuroblastic counterpart (SH-SY5Y) or the parental SK-N-SH population. In addition to confirming reports of clinical efficacy of the various classes of agents, these data have demonstrated a variation in response possibly related to type or degree of neuronal differentiation and emphasize the importance of understanding the phenotypic diversity commonly observed in neuroblastoma.