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Cross‐resistance between different classes of anti‐neoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross‐resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF‐CEM cells developed for resistance to VP. The resistant cells also displayed 14‐ and twofold resistance to cytarabine (ara‐C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIα (P < 0·001) and β protein (P < 0·026), formed substantially lower amounts of the topo II–DNA complex, and had a markedly decreased level of Fas (CD95/APO‐1)‐ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/efflux of …