The efficacy of killing human cancer cells by a modified Herpes-simplex-virus thymidine kinase TK.007/ganciclovir (GCV) system was investigated in malignant cells of different histogenetic origin. The aim was to determine whether different histogenetic origins of cancer cells in them-selves influence their reaction towards an approach of synthetic lethality, which theoretically should be applicable independently of the cell type. Fifteen malignant human cell lines were transduced with a lentiviral vector to stably express the TK.007 gene and cell proliferation assays under GCV were performed. Among TK.007-expressing cell lines, lymphoma and leuke-mia cells were more susceptible to killing than solid cancer cells, while osteosarcoma and mela-noma cells exhibited an intermediate susceptibility. Similar differences in killing were also noted in wild-type non-transduced cells. This study highlights that the histogenetic origin of malignant cells strongly influences their susceptibility towards cytotoxic agents, with leukemias and lym-phomas being more sensitive than solid cancer cells.