Cytotoxic effects of hyperthermia, 5-fluorouracil and their combination on a human leukemia T-lymphoblast cell line, CCRF-CEM.
ABSTRACT The cytotoxic effects of 5-fluorouracil (FUra), hyperthermia, and the combination of these treatments were examined in a human T-lymphoblast cell line, CCRF-CEM. Simultaneous exposure of exponentially growing CCRF-CEM cells to hyperthermia (39 and 42 degrees C) and FUra (10, 50, and 100 microM) for 1 or 2 hr resulted in subadditive or additive cell kill. When CCRF-CEM cells were exposed to these agents in sequence (hyperthermia----FUra and FUra----hyperthermia) for 1 and 2 hr duration additive cell kill was also observed. Enhanced cytotoxic effects were observed when a longer exposure (4 and 8 hr) to FUra (100 microM) followed heat (42 degrees C for 1 and 2 hr). Heat exposure (42 degrees C, 1 and 2 hr) induced a rapid decrease in the synthesis of DNA of CCRF-CEM cells, followed by a rebound increase at 12 hr and a new decrease at 24 hr. Flow cytometry demonstrated an accumulation of cells in the S phase at 12 hr after heat exposure, followed by a marked increase of the G + M population (maximum at 24 hr). The exposure time, and the sequence of administration of hyperthermia and FUra were critical determinants of cytotoxicity in this in vitro system and might constitute important variables of treatment when these two agents are used clinically.
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ABSTRACT: In a series of studies to investigate activation energies and thermal enhancements of various chemotherapeutic agents the effect of 5-fluoruracil (5FU), an antimetabolite, on murine tumour cells was studied at elevated temperatures. Animal tumours were early generation isotransplants of a spontaneous fibrosarcoma, FSa-II tumours, and C3Hf/Sed mice were used throughout. Cell survival curves for 5FU were obtained as a function of treatment time by in vitro treatment-in vivo lung colony assay at temperatures between 37.0 and 43.5 degrees C. The D0, or the treatment time to reduce surviving fraction from S to S/e in the exponential portion of the survival curve, decreased slightly from 37 degrees C treatment to 41.5 degrees C treatment. The D0 decreased substantially from 41.5 degrees C to 43.5 degrees C. Arrhenius-plot analysis indicated that the activation energies were 92.9 and 731 kJ/M at temperatures between 37 and 41.5 degrees C, and between 41.5 and 43.5 degrees C, respectively. The activation energy of 92.9 kJ/M for the temperature range from 37 to 41.5 degrees C was the lowest of the other agents, bleomycin, cis-diamminedichloroplatinum and 1,3-bis(2-chloroethyl)-N-nitrosourea, which have been investigated in our laboratory. This indicated that the thermal enhancement was smallest among these agents. In vivo experiments failed to demonstrate thermal enhancement of the anti-tumour effect of 5FU. Namely, combined 5FU and heat treatments at 41.5 and 43.5 degrees C did not prolong the tumour growth time compared with 5FU given at room temperature. No pH effect was found in an in vitro experiment and glucose administration did not enhance the anti-tumour effect of 5FU.International Journal of Radiation Biology 02/1991; 59(1):239-49. · 1.84 Impact Factor
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ABSTRACT: In vitro and clinical studies have shown antineoplastic effects of hyperthermia alone and in combination with other treatment modalities. Synergistic cytotoxic effects of chemotherapy and hyperthermia have been demonstrated on leukemic cell clones in vitro. It seems that hyperthermia is effective in overcoming chemotherapy resistance. Several groups treated solid tumors by using total body hyperthermia (TBHT). However, only a few studies have been reported investigating the clinical effects of TBHT in myeloproliferative disorders. We report the case of a 7-year-old boy with myelomonocytic leukemia treated with TBHT (2 hours, 42°) combined with etoposide (600 mg/m2), melphalan (30 mg/m2) and hyperglycemia (200-300 mg/dl). Within 24 hours after TBHT, the leukemic cells decreased after TBHT from 53,000/μl to zero. Skin leukemic infiltrates, resistant to conventional treatment, also responded well. Although our patient relapsed 34 days after TBHT, these results indicate that TBHT in combination with cytotoxic treatment may be a useful treatment modality in refractory leukemia.Medical and Pediatric Oncology 07/2006; 22(1):61 - 65.
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ABSTRACT: It has been demonstrated in vitro and in vivo that hyperthermia can enhance the cytotoxicity of some chemotherapeutic agents. This paper summarizes the authors' own laboratory studies on the effect of chemotherapeutic agents given at elevated temperatures, experimental results obtained using animal tumour systems in other laboratories, and clinical trials of thermochemotherapy reported in literature. The in vivo studies have demonstrated that the thermal enhancement of cytotoxicity of many chemotherapeutic agents is maximized at mild temperatures such as at 40.5-43oC. Comparison of in vitro and in vivo results using five agents show that the in vivo thermal enhancement increases with an increase in the activation energy obtained in the temperature range between 40.5 and 43.0oC. A summary of experimental results obtained by various investigators indicates a potentially wide variation in the thermal enhancement of a given agent among the different types of tumours and suggests potential agents useful at moderately elevated temperatures. In vivo studies on nine different agents indicate that the drug(s) of choice at physiological temperatures may not be the drug(s) of choice at elevated temperatures. It is also shown that drug concentration in the target must be high for sufficient thermal enhancement. Clinical trials of thermochemotherapy have employed various heating methods, including local heating, hyerthermic perfusion and whole body hyperthermia. Extensive trials have been made in the treatment of melanoma and soft tissue sarcoma in the extremity. Hyperthermic isolated perfusion with chemotherapeutic(s) provides much higher drug concentration than a systemic drug administration in the target(s), resulting in a high tumour response rate and an increased survival of the patients. It is of interest that the most successful agent used in the treatment of both melanomas and sarcomas is melphalan and is the drug of choice at moderately elevated temperatures among the nine agents tested in the in vivo studies. Current results using the tumour necrosis factor with melphalan are impressive. In several institutes, techniques have been developed to uniformly heat the localized tumour, but studies are needed to find an agent effective at elevated temperatures to each type of tumours and to establish the methods for obtaining a sufficient drug concentration in the target tissue.International Journal of Hyperthermia 01/1999; 15(2):79-107. · 2.77 Impact Factor