International journal of cancer. Journal international du cancer
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Glutathione (GSH) has often been implicated in the mechanism of resistance to platinum anti-cancer drugs. It has been suggested that GSH may reduce the cytotoxicity of these drugs by forming inactive conjugates and by enhancing the repair of DNA-platinum crosslinks. In the present study we have examined the effect of D,L-buthionine-S,R-sulfoximine (BSO) pretreatment on the accumulation of platinum in a sensitive (CHI) and 2 relatively resistant (SKOV-3, HX/62) human ovarian-carcinoma cell lines following exposure to PtII- (cisplatin, carboplatin) and PtIV-drugs (tetraplatin). ⋯ However, concomitant increases in intracellular levels of reactive species were observed only after tetraplatin exposure. Our data suggest that the greater potentiation of PtIV- compared with PtII-drug cytotoxicity in the relatively resistant cell lines following 24 hr BSO pre-treatment may be caused by a differential effect of BSO on the metabolism and cellular distribution of these drugs. A BSO-induced reduction in PtII- but not PtIV-drug accumulation in these cells may also partially contribute to the differential potentiation of cytotoxicity of these drugs.
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In a hospital-based case-control study of ovarian cancer conducted in Athens (1989-1991), 189 women with histologically confirmed common malignant epithelial tumors of the ovary were compared with 200 hospital visitor controls. All interviews were conducted by personal interview in the 2 participating hospitals and the data were analyzed by modelling through logistic regression, controlling for demographic and reproductive variables. ⋯ There was a statistically significant (p for trend 0.007) and a dose-dependent association between hair dyeing and risk of ovarian cancer. Compared to never-users, women dyeing their hair up to 4 times per year had a relative risk of 1.74 (0.91 to 3.32) whereas those dyeing their hair 5 or more times per year had a relative risk of 2.16 (1.19 to 3.89).
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The relationship between reproductive variables (parity, age at first birth, number of induced and spontaneous abortions) and cancer risk has been analysed using data from an integrated series of case-control studies conducted in northern Italy between 1983 and 1992. The overall data-set included women below age 75 with histologically confirmed cancers of the following sites: oesophagus, 58; stomach, 280; colon, 405; rectum, 210; liver, 82; gall-bladder, 29; pancreas, 129; breast, 3,415; cervix, 742; endometrium, 725; ovary, 953; bladder, 68; kidney, 56; thyroid, 180; lymphomas, 80; myelomas, 57; and a total of 5,619 controls admitted to hospital for acute non-neoplastic, non-gynaecological, non-hormone-related conditions. Multivariate odds ratios, as estimators of relative risks (RR), were obtained after allowance for age, education, use of oral contraceptives and oestrogen replacement treatments, plus various reproductive factors. ⋯ For induced abortions, there was a strong inverse trend in risk for endometrial cancer (RR = 0.5), and the RRs were below unity also for colon and breast cancer. In contrast, cervical cancer was directly associated with the number of spontaneous abortions. Although the underlying aetiological interpretations are different for various cancer sites, this study provides, in a large and uniform data-set, quantitative information on the long-term impact of reproductive factors on cancer risk.
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Human tumor-infiltrating lymphocyte (TIL) cytotoxicity facilitated by anti-T-cell receptor antibody.
Long-term growth of tumor-infiltrating lymphocytes (TIL) in high concentrations of rIL-2 is required for generation of therapeutic numbers of cells for adoptive immunotherapy of human cancer. Under these conditions rIL-2 promotes both anti-tumor cytotoxicity and lymphocyte growth from tumors of several histological types. In a series of 16 consecutive tumors, studies of TIL-mediated cytotoxicity against different tumor targets were characterized by an initial strong tumor-non-specific cytotoxicity. ⋯ Both CD4 and CD8 populations expressed TcR antigen reactive with anti-TcR antibody. These results indicate that, despite poor in vitro anti-tumor cytotoxicity in short-term assays, CD8+ TIL are fully competent cytotoxic effector cells when subjected to strong activation signals via the TcR complex. In addition, these results imply that adoptively transferred CD4+ populations of TIL have in vivo biologic functions quite distinct from those of CD8+ populations and, further, that disparate clinical outcomes could reasonably be expected from the adoptive transfer of either population alone.
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The role of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) in monocyte-mediated up-regulation of lymphokine-activated killer (LAK) cell induction by IL-2 was examined. Treatment of blood mononuclear cells (MNC) of healthy donors with GM-CSF for 4 days in the presence of IL-2 resulted in a significant increase in LAK activity against natural killer (NK)-resistant Daudi cells, as assessed by the 4 hr 51Cr-release assay. For determination of the role of GM-CSF in LAK induction, highly purified lymphocytes (greater than 99%) and monocytes (greater than 90%) were isolated from MNC by counter-flow centrifugal elutriation (CCE). ⋯ Treatment with anti-GM-CSF antibody completely abolished up-regulation of LAK induction by GM-CSF-treated monocytes. When blood monocytes were separated into 5 fractions by CCE, GM-CSF-responding monocytes were found to be responsible for up-regulation of LAK induction. These results suggest that GM-CSF may be important in monocyte-mediated up-regulation of LAK cell induction in vivo.