Metastatic testis tumours, in contrast to most other types of cancer, can be cured by drugs. To investigate which classes of chemotherapeutic drug are differentially toxic to testis-tumour cells, we compared the in vitro dose-response curves of 5 human testis and 5 bladder-cancer cell lines to 12 compounds. The testis cells were hypersensitive to drugs that interact directly with DNA (m-amsa, bleomycin, cisplatin, doxorubicin, methylnitrosourea, mitozolomide, etoposide, mitomycin-C), but little or no difference between the 2 cell types was seen following exposure to drugs whose mechanisms of action do not involve direct interaction with DNA (methotrexate, 5-fluorouracil, colchicine, vinblastine). We conclude that testis tumour cells are either less tolerant of, or have a reduced capacity to repair, DNA damage.
The relative importance of two variables, drug concentration and period of exposure, in relation to the therapeutic potential of intravesical chemotherapy was examined in an experimental system. A human bladder cancer cell line was exposed to a range of concentrations of the four drugs commonly used to treat superficial bladder cancer (adriamycin, epodyl, mitomycin-c, thiotepa) for periods of 30, 60 and 120 min. An exponential relationship was observed between clonogenic cell kill and both drug concentration and period of exposure. Thus, under the experimental conditions employed, cytotoxicity is proportional to dose (i.e. concentration X period of exposure). These two variables are of equal importance in relation to tumor cell kill, indicating that maximum therapeutic benefit may be obtained by using the highest concentration achievable for as long as the patient can retain the instillate, bearing in mind the potential increase in toxicity to the patient and the cost.
Summary The DNA repair enzyme, 06-alkylguanine-DNA-alkyltransferase (ATase), is thought to be the principal mechanism controlling resistance to nitrosoureas and related alkylating agents. We compared the sensitivities of five human testis and five bladder tumour cell lines to two nitrosoureas (N-nitroso-Nmethylurea (MNU) and mitozolomide) with cellular levels of ATase. Enzyme levels ranged from 3 to 206 fmol mg-1 protein (0.1 x 104 to 5.1 x 104 molecules/cell) in the testis lines and from 11 to 603 fmol mg-1 (0.4 x 104 to 9.1 x 104 molecules/cell) in the bladder lines. Based on IC5Os in an MTT assay, the testis tumour cell lines were, on average, four times more sensitive to MNU and six times more sensitive to mitozolomide than the bladder cell lines. The cytotoxicities of MNU and mitozolomide were closely related (R = 0.9). In the testis cell lines ATase activity (molecules/cell) was related to IC50s for mitozolomide (R = 0.97) but not MNU (R = 0.78). In the bladder cell lines and overall, ATase activity correlated with cellular sensitivity to neither agent. Relatively high levels of resistance occurred in cells expressing low levels of ATase, and amongst cell lines expressing high levels of ATase, large differences in IC5Os were observed. These results support the suggestion that resistance to nitrosoureas can be mediated by mechanisms other than ATase and that at relatively high levels of expression, ATase does not confer resistance in proportion to its activity.Cells expressing ATase are commonly resistant to the cytotoxic effects of mono-and bifunctional methylating and chloroethylating agents (Pegg, 1990), including the chloroethylnitrosoureas (CNUs) used as chemotherapeutic drugs. ATase is thought to reduce the cytotoxicity of these agents by transferring the chloroethyl group from the o6 position of guanine to a cysteine residue in the active site of the enzyme before interstrand crosslinks can be formed (Kohn, 1977;Erickson et al., 1980a;1980b). Each enzyme molecule can remove only one alkyl group, as the reaction is autoinactivating (Pegg, 1990). This may be of clinical relevance as it has been suggested that tumours with low levels of this enzyme are more likely to respond to chemotherapy using nitrosoureas.There are three main lines of evidence indicating that ATase influences sensitivity to nitrosoureas. Firstly, cultured cells expressing low levels of the enzyme can be hypersensitive to nitrosoureas (Day et al., 1980;Bodell et al., 1986;Jelinek et al., 1988;Smith & Brent, 1989), though this is not always the case (Samson & Linn, 1987;Maynard et al., 1989). Secondly, pretreatment of cells with agents which deplete endogenous ATase, such as alkylating agents or 06_ methylguanine as free base, increases sensitivity to subsequent exposure to alkylating agents (Gibson et al., 1986;Gerson et al., 1988 The abbreviations used are: BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; EDTA, ethylenediaminetetra-acetic acid, disodium salt; IC50, drug concentration causing a 50% decrease in optical density com...
There is evidence that dimethyl sulfoxide (DMSO) can increase the anticancer activity of chemotherapeutic drugs. As DMSO is instilled into the bladder for interstitial cystitis, it could be readily adopted in clinical practice if it was found to enhance the effectiveness of the drugs used for intravesical chemotherapy. The purpose of this study was to investigate, using a human bladder cancer cell line, the hypothesis that DMSO enhances the activity of these agents. However, the addition of 4% DMSO to the four drugs most frequently used for intravesical chemotherapy (adriamycin, epodyl, mitomycin-c, thiotepa) did not increase tumour cell kill in vitro.
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