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.
[Show abstract][Hide abstract] ABSTRACT: Thermal radiosensitization was studied in two human T-cell acute lymphoblastic leukemia cell lines (JM and MOLT3) with regard to heat-irradiation sequence and heating duration. In MOLT3 thermal radiosensitization was maximal when 43.5 degrees C hyperthermia immediately preceded or followed irradiation; at 41.5 degrees C, radiosensitization was maximal with hyperthermia immediately before or up to 3 h after irradiation. In JM, enhancement of radiation killing was unexpectedly maximal when 41.5 or 43.5 degrees C hyperthermia preceded irradiation by 2 to 4 h. Thermal radiosensitization increased exponentially with increasing duration of heating at 41.5 degrees C for at least 3 h in MOLT3. In contrast, in JM, radiosensitization increased exponentially for 1.6 h but additional heating (up to 3 h net heating) had no appreciable further effect on radiation killing. For JM, repair of single and double stranded DNA breaks was investigated using alkaline and neutral elution techniques to determine whether the unusual results regarding heat-irradiation sequencing were related to effects of heat on repair of DNA damage. These studies were unable to detect significant differences in repair of single or double stranded DNA breaks between unheated control cells and cells heated at 41.5 degrees C for 1 h ending 4 h before irradiation. The direct cytotoxicity of hyperthermia was also studied in both cell lines.
Cancer Research 08/1988; 48(13):3576-80. · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During clinical hyperthermia, various blood elements may be exposed to elevated temperatures. The effect of heat on human lymphocyte viability and human lymphoblastoid cell viability and growth was therefore measured. In the viability studies, cells were heated for different times and temperatures and stained with fluorescein diacetate either immediately of at various times after treatment; dye uptake was then analysed using fluorescence microscopy. There was no significant decrease in lymphocyte viability when assayed at 0 and 24 h after heating at 42-43 degrees C for varying times. Similarly, when proliferating lymphoblastoid cells were heated at 42-43 degrees C, there was no decrease measured in viability immediately after heating. However, in contrast to the lymphocyte results, a progressive decrease of lymphoblastoid cell viability was observed with increasing time after treatment. A nadir in viability was observed 48-72 h after heating, followed by a subsequent apparent recovery. This recovery showed a correlation with cell growth, as well as lysis of non-viable cells. The cell population doubling time was also lengthened, with longer doubling times observed for more severe heat treatments.
International Journal of Hyperthermia 01/1991; 7(6):849-56. DOI:10.3109/02656739109056453 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: After more than three decades since their introduction, fluoropyrimidines, especially FUra, are still a mainstay in the treatment of various solid malignancies. The antitumor effects of fluoropyrimidines are dependent upon metabolic activation. FdUMP, FUTP and FdUTP were identified as the key cytotoxic metabolites that interfere with the proper function of thymidylate synthase and nucleic acids. The relevance of these metabolites is cell-type specific. Recently, fluorouridine diphospho sugars have been detected, but the precise function of this class of metabolites is currently unknown. In mammalian systems fluoropyrimidines and their natural counterparts share the same metabolic pathways since the substrate properties in enzyme-catalyzed reactions are frequently comparable. Ongoing studies indicate that the metabolism and action of fluoropyrimidines exhibit circadian rhythms, which appear to be due to variations in the activity of metabolizing enzymes. Essential for the expanding knowledge of the pathways and effects of fluoropyrimidines has been the constant improvement of analytical methods. These include ligand binding techniques, numerous dedicated HPLC systems and 19F-NMR. Because the overall response rates achieved with fluoropyrimidines are modest, strategies based on biochemical modulation have been devised to enhance their therapeutic index. Biochemical modulators include a wide range of various compounds with different modes of action. In recently completed clinical trials, combinations of FUra with leucovorin, a precursor for 5,10-methylene tetrahydrofolate, or with levamisole, an anthelminthic with immunomodulatory activity, appeared to be superior to FUra alone. At the preclinical level combinations of fluoropyrimidines with, e.g. interferons or L-histidinol were demonstrated to be interesting candidates for further testing. The future therapeutic utility of fluoropyrimidines will depend on both the improvement of combination regimens currently used in the treatment of cancer patients and the judicious clinical implementation of promising experimental modulation strategies. Moreover, novel fluoropyrimidines with superior pharmacological properties may become important as part of or instead of modulation approaches.
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