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Enhanced Toxicity for Mice of Combinations of Bacterial Endotoxin with Antitumor Drugs

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Enhanced Toxicity for Mice of Combinations of Bacterial Endotoxin with Antitumor Drugs ANTIMrCROBIAL AGENTS AND CHEMOTHERAPY, May 1973, p. 599-606 Vol. 3, No. 5 Copyright 0 1973 American Society for Microbiology Printed in U.SA. Enhanced Toxicity for Mice of Combinations of Bacterial Endotoxin with Antitumor Drugs NELDA M. MARECKI AND S. G. BRADLEY Department of Microbiology, Virginia Commonwealth University, Richmond, Virginia 23298 Received for publication 6 February 1973 The toxicity of Salmonella typhosa 0901W endotoxin to mice was potentiated by (per kilogram) 1 mg of colchicine, 20 mg of emetine, 100 mg of 6-mercaptopu- rine, 100 mg of 6-methylmercaptopurine riboside, 75 mg of methotrexate, 2 mg of sparsomycin, or 2.5 mg of vinblastine. No potentiation of endotoxin lethality was evident with simultaneously administered (per kilogram): 200 mg of cytosine arabinoside, 450 mg of dibromomannitol, 100 mg of 5-fluorouracil, 125 mg of 5-fluorouracil deoxyriboside, 8 mg of mitomycin C, 1 mg of nitrogen mustard, or 10 mg of tris(1-aziridinyl)-phosphine sulfide. With the exception of colchicine, all drugs prolonged the duration of sleep after the administration of 80 mg of hexobarbital per kg. Simultaneous injection of endotoxin with 100 mg of 6-mercaptopurine per kg, 75 mg of methotrexate per kg, or 1 mg of vincristine per kg resulted in significantly greater lethality than administration either prior to or after the drug. However when endotoxin was administered prior to 100 mg of 5-fluorouracil per kg, lethality was significantly increased. The route of adminis- tration of endotoxin and 5-fluorouracil, 6-mercaptopurine, methotrexate, or vincristine did not influence overall lethality. Pretreatment of mice with multiple doses of Escherichia coli endotoxin resulted in a significant reduction in the lethality of 6-mercaptopurine- or vincristine-endotoxin combinations, but had no influence on 5-fluorouracil- or methotrexate-endotoxin combinations. Endotoxin- pretreated mice were more susceptible to vincristine alone and more resistant to high doses of 5-fluorouracil. The lethality of 6-mercaptopurine was increased by simultaneous administration of gram-negative isolates from feces of human patients with neoplastic disease. The increased lethality associated with com- microsomal enzymatic activity was obtained by binations of bacterial endotoxins and various measuring the duration of hexobarbital-induced drugs has been recognized for some time. Berry sleep 1 day after, or with, concurrent drug (2) found that actinomycin D potentiated the administration. effects of endotoxin, and this interaction has Based on the results of these studies and been used as a sensitive assay for endotoxin (3, those reported by Rose et al. (12, 13), 5-fluorou- 7). Karp and Bradley (5) demonstrated an racil, 6-mercaptopurine, methotrexate, and vin- interaction with both pactamycin and spar- cristine were chosen for further studies about somycin, and endotoxin. Subsequently, a num- the mechanism of action of the drug-endotoxin ber of antineoplastic agents and bacterial en- synergy. The effects of the sequence and route of dotoxin have been demonstrated to interact drug and endotoxin administration were eval- synergistically in vivo (11-13). uated. The capability of endotoxin pretreat- In this study, the ability of colchicine, cyto- ment to mitigate the synergistic interaction was sine arabinoside, dibromomannitol, emetine, examined. Gram-negative isolates from feces of 5-fluorouracil, 5-fluorouracil deoxyriboside, 6- human patients with neoplastic disease were mercaptopurine, 6-methylmercaptopurine ribo- used as a source of endotoxin for interaction side, methotrexate, mitomycin C, nitrogen with 6-mercaptopurine. mustard, sparsomycin, tris(1-azirdinyl)-phos- phine sulfide, and vinblastine to enhance en- MATERIALS AND METHODS dotoxin lethality in mice was evaluated. An BALB/c male mice weighing 22 to 27 g were used in indication of the effect of each agent on hepatic all experiments. Mice were obtained from Battelle 599 600 MARECKI AND BRADLEY ANTIMICROB. AG. CHEMOTHER. Memorial Institute, Laboratory Supply Co., Inc., and (0.5 and 0.3%, respectively) broth at 37 C, harvested ARS/Sprague-Dawley. With the exception of di- by centrifugation, suspended in sterile 0.15 M NaCl, bromomannitol (NCS-94100), all drug solutions were and adjusted to an optical density of 0.3 (420 nm). prepared so that 0.01 ml per g of mouse weight would Bacterial numbers were quantitated by the pour-plate provide the desired dose when administered. Colchi- method. Colonies were counted after 48 h of incuba- cine (Nutritional Biochemicals Corp., Cleveland, tion at 37 C on peptone-yeast extract agar. The mean Ohio), cytosine arabinoside (NSC-63878), emetine lethal dose (LD50) for mice of each bacterial strain was (NSC-33669), 5-fluorouracil (NSC-19893), 5-fluoro- determined 3 days after injection. uracil deoxyriboside (NSC-27640), 6-mercaptopurine The LD50 of each drug was determined by the (NSC-755), 6-methylmercaptopurine riboside method of Reed and Muench (9) and, where applica- (NSC-40774), methotrexate (NSC-740), mitomycin C ble, by interpolation of probit plots (6). Synergy was (NSC-26980), nitrogen mustard (NSC-762), spar- determined by analysis of isobolograms. The tests for somycin (The Upjohn Company, Kalamazoo, Mich.), parallelism and calculation of potency ratios and tris(1-aziridinyl)-phosphine sulfide (thio-TEPA) confidence limits were done by the method of Litch- (NSC-6396), vinblastine (NSC-49842), and vincris- field and Wilcoxon (6). "One-tailed" Student's t tests tine (NSC-67574) were dissolved or suspended in were used to evaluate differences in duration of sterile distilled water and adjusted to pH 7. Due to the barbiturate-induced sleep between test and control low solubility of dibromomannitol, it was necessary to mice. The significance of differences between the use a stock solution of 15 mg/ml for injections (0.75 ml proportion of dead mice in the test and control groups per 25-g mouse yields 450 mg/kg). Salmonella typhosa was evaluated by the chi-square test. The acceptable 0901W lipopolysaccharide (Difco), and Escherichia level of significance was P < 0.05 in all statistical coli 026:B6 B lipopolysaccharide (Difco) were sus- tests. pended in 0.15 M NaCl. All drug and endotoxin injections were given simultaneously via the in- traperitoneal (i.p.) route unless otherwise indicated. RESULTS The duration of hexobarbital-induced sleep was The LD50 for S. typhosa 0901 endotoxin was determined after i.p. injection of 80 mg of hexobarbi- 13.5 mg (11.25-16.20) per kg by probit plot tal per kg (Winthrop Laboratories, New York, N.Y.). analysis and 13.8 mg/kg by Reed-Muench deter- The duration of sleep was defined as that interval A 4 between the loss and the restoration of the righting mination. dose of mg of endotoxin per kg reflex (the ability or disability to right themselves resulted in less than 5% lethality. The LD,0 for twice within a 10-s period). E. coli 026:B6 endotoxin was 8.1 mg/kg by Pretreatment of mice with E. coli endotoxin was Reed-Muench determination. carried out as follows: 1 mg of endotoxin per kg on day Of the 14 drugs evaluated in this study, 7 -6, 2 mg of endotoxin per kg on days -5 and -4, and markedly potentiated the lethal effects of en- 4 mg of endotoxin per kg on day -3. The mice were dotoxin (Table 1). In mice receiving simultane- challenged on day zero. ous injections of endotoxin and (per kilogram) 1 The cultures of E. coli 06, E. coli HB, Klebsiella mg of colchicine, 20 mg of emetine, 100 mg of pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa used in these studies were all isolated from 6-mercaptopurine, 100 mg of 6-methylmercap- rectal samples obtained from cancer patients, and topurine riboside, 75 mg of methotrexate, 2 mg maintained on nutrient agar (Difco). With the excep- of sparsomycin, or 2.5 mg of vinblastine, the tion of E. coli HB, all cultures were kindly supplied by potentiations of endotoxin lethality were statis- Viola Young of the National Cancer Institute. Cul- tically significant (P < 0.05) (Table 1). These tures were grown overnight in peptone-yeast extract potentiations occurred in a parallel manner TABLE 1. Potentiation of the toxicity of S. typhosa endotoxin by antitumor drugs Percent dead Fold decrease Drug due to drug Endotoxin LD.. in endotoxin Slope of potentiation alonea LD5 None 13.5 (11.25-16.20) 1.0 1.87 (1.55-2.26) Colchicine, 1 mg/kg 1 0.41 (0.29-0.61) 32.9 1.86 (1.27-2.72)b Emetine, 20 mg/kg 10 0.17 (0.09-0.32) 79.4 7.63 (3.32-17.67) 6-Mercaptopurine, 100 mg/kg 0 0.58 (0.37-0.90) 23.2 2.11 (1.70-2.62)b 6-Methylmercaptopurine ribo- 0 0.26 (0.18-0.39) 51.9 1.54 (1.18-2.00)b side, 100 mg/kg Methotrexate, 75 mg/kg 10 1.33 (0.95-1.86) 10.15 1.72 (1.26-2.36)" Sparsomycin, 2 mg/kg 18 0.07 (0.03-0.16) 195.65 11.80 (2.27-61.36) Vinblastine, 2.5 mg/kg 0 0.77 (0.41-1.87) 17.5 3.88 (1.49-10.09) L L a Cumulative percent dead as of day that potentiation was calculated. 'Potentiated response was parallel (P < 0.05) to the dose-response curve of endotoxin alone. VOL. 3, 1973 TOXICITY OF ENDOTOXIN AND ANTITUMOR DRUGS 601 when colchicine, 6-mercaptopurine, 6-methyl- The lethality of various combinations of en- mercaptopurine riboside, or methotrexate was dotoxin and 6-mercaptopurine is presented dia- the potentiating agent. grammatically by means of an isobologram The diagrammatic presentation of data for (Fig. 2). It is obvious from such a representation the 6-mercaptopurine potentiation of endotoxin that the lethality of the various combinations lethality (Fig.
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