Cancer chemotherapy reports最新文献

Inhibition of the deamination of 14C-cytosine arabinoside by two lots of tetrahydrouridine was studied in monkey serum. The average inhibition of deaminase activity was 78% for tetrahydrouridine lot AJ39 (1.0 muM) when the concentration of cytosine arabinoside ranged from 44.2 to 170.7 muM; under the same conditions tetrahydrouridine lot AJ22 inhibited deamination by an average of 68%. Apparent Ki values were 0.26 muM for AJ39 and 0.43 muM for AJ22. The assay may be used to check the relative biologic activity of various lots of tetrahydrouridine.

Inosine dialdehyde, an antitumor agent highly active against several murine tumors, ispresently undergoing clinical trial for potential activity in man. To aid in the clinical evaluation of this drug, a chemical assay has been developed for the determination of concentrations of inosine dialdehyde in biologic fluids. The method involves reaction of inosine dialdehyde with phenylhydrazine in an acetic acid medium, followed by extraction of the product into ether and determining its absorbance at 378 nm. The reaction is specific for free inosine dialdehyde and will quantitate amounts as low as 1.0 mug.

A cell cycle stage-specific multicompartmental model has been developed and used to investigate the effects of antitumor drugs on the proliferation of tumors. The drug effects simultaneously considered are (a) non-cycle-specific killing and cycle stage-specific killing of cells, (b) progression delay of cells through the cell cycle phases which may bring about an accumulation of cells in various phases of the cell cycle, and (c) prolongation of cell cycle times. These effects are analyzed in terms of possible variations in the behavior of cell kinetic parameters (namely, cell cycle times, cell loss rate, and growth fraction) and are implemented in the model specifying proper functional forms for the parameters. The time-course of drug distribution in a tumor-host system is also described by a two-compartment model and the factors affecting drug action are quantitatively formulated as a function of drug concentration. Simulation is carried out to examine the effects of BCNU, cytosine arabinoside, and methotrexate on the cell cycle and proliferation kinetics of L1210 leukemia, and the results of the simulation compare favorably with available experimental data. Also discussed are the sensitivity of drug effects to variation in dosage schedule and the different nodes of drug actions exerted on each cell cycle phase.

The cardiotoxicity of seven anthracycline antibiotics was evaluated in small groups of rats treated with repeated intraperitoneal injections. The electrocardiogram showed a widening of the QRS complex often with the appearance of a distinct S-wave trough and occasionally with an increase or flattening of the T wave. Ventricular extrasystoles, intraventricular block, bradycardia, and heart failure developed either during treatment or after discontinuation of therapy. Based on the cumulative dose required to induce significant electrocardiographic changes, the compounds were ranked in the following order of decreasing cardiotoxicity: adriamycin, daunorubicin, NSC-149584, rubidazone, NSC-143496, daunomycin-semicarbazone, and NSC-118714. For three of these compounds used in humans (adriamycin, daunorubicin, and rubidazone) the rat screening results are in good agreement with the clinically observed cardiotoxicity.

The new semisynthetic epipodophyllotoxin, 4'-demethylepipodophyllotoxin 9-(4,6-o-ethylidene- beta-D-glucopyranoside) (NSC-141540), was tested for antitumor activity against solid tumors and for clinical toxicity in 30 patients. The first two courses were given intravenously (60 mg/m2/day times 5, every 21 days), and subsequent courses were given orally (60-120 mg/m2/day times 5, every 21 days). The drug was subjectively well tolerated but induced considerable leukothrombocytopenia and alopecia. It demonstrated significant activity in oat cell carcinoma of the lung (eight responses out of 11 patients) and ovarian cancer (-our responses out of six patients). NSC-141540 has valuable cytostatic activity against these two tumors and warrants further clinical trials, especially in combination chemotherapy.

Specific biochemical molecules used as potential biologic markers, including modified nucleosides, polyamines, and pyrimidine catabolic end-products, were quantitatively measured in the urine of seven patients with Burkitt's lymphoma before, during, and after one or more courses of therapy. The results of this preliminary study demonstrated that patients with this disease frequently excrete significantly increased amounts oof modified nuceleosides (considered to be derived primarily from transfer ribonucleic acid), polyamines, and beta-aminoisobutyric acid during the course of their disease. With successful treatment and rapid destruction of tumor cells, a concomitant rise in these molecules occurs. Elevations were observed prior to chemotherapy and changes in levels associated with treatment or tumor progression appeared to correlate with disease status and to aid in assessing antitumor response. Periodic follow-up analysis of these molecules may be helfful in appraising relapse or recurrence of the malignancy prior to overt evidence of tumor by existing clincial means.