ABSTRACT
17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a new anticancer agent currently in clinical trials. The ability of 17-AAG to abrogate the function of heat-shock protein Hsp90 and modulate cellular sensitivity to anticancer agents has prompted recent research to use this compound in drug combination therapy. Here we report that 17-AAG has striking opposite effects on the activity of arsenic trioxide (ATO) and ara-C. Combination of 17-AAG with ATO exhibited a synergistic effect in leukemia cells, whereas coincubation of 17-AAG and ara-C showed antagonistic activity. Mechanistic studies revealed that ATO exerted cytotoxic action by reactive oxygen species generation, and activated Akt survival pathway. 17-AAG abrogated Akt activation and enhanced the activity of ATO. In contrast, treatment of leukemia cells with 17-AAG caused a G1 arrest, a decrease in DNA synthesis and reduced ara-C incorporation into DNA, leading to antagonism. The ability of 17-AAG to enhance the antileukemia activity of ATO was further demonstrated in primary leukemia cells isolated from patients with acute myeloid leukemia and chronic lymphocytic leukemia, including cells from refractory patients. Our data suggest that combination of 17-AAG and ATO may be an effective therapeutic regimen. Caution should be exercised in using 17-AAG together with ara-C, as their combination effects are schedule dependent.
Subject(s)
Antineoplastic Agents/pharmacology , Arsenicals/pharmacology , Benzoquinones/pharmacology , Cytarabine/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Lactams, Macrocyclic/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Myeloid/metabolism , Oxides/pharmacology , Acute Disease , Apoptosis/drug effects , Arsenic Trioxide , Arsenicals/antagonists & inhibitors , Cytarabine/antagonists & inhibitors , DNA/biosynthesis , DNA/drug effects , DNA/metabolism , Drug Administration Schedule , Drug Antagonism , Drug Screening Assays, Antitumor , Drug Synergism , Drug Therapy, Combination , G1 Phase/drug effects , HSP90 Heat-Shock Proteins/physiology , HeLa Cells , Humans , Jurkat Cells , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Myeloid/drug therapy , Oxides/antagonists & inhibitors , Sensitivity and Specificity , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Liposomal amphotericin B (L-AmB) is emerging as one of the most attractive new antifungal agents. We have attempted to show that phagocytic cells circulating in blood play an important role in transport and accumulation of L-AmB at inflammatory sites in vivo. Free AmB or L-AmB was injected intravenously to mice, and the amount of AmB in peritoneal exudate cells was quantitated by high-performance liquid chromatography. Higher levels of AmB were detected in a higher number of mice injected with L-AmB. The presence of L-AmB in inflammatory peritoneal cells after intravenous administration of fluorescence-labeled L-AmB also suggested that macrophages play an important role in the transport of intravenously administered L-AmB to inflammatory sites.
Subject(s)
Amphotericin B/administration & dosage , Macrophages, Peritoneal/metabolism , Amphotericin B/metabolism , Animals , Ascitic Fluid/cytology , Chromatography, High Pressure Liquid , Drug Carriers , Exudates and Transudates/cytology , Fluorescence , Humans , Injections, Intravenous , Liposomes , MiceABSTRACT
We compared MICs and MBCs of various free- and liposome-incorporated antimicrobial agents against several patient isolates of Mycobacterium avium-M. intracellulare complex and certain American Type Culture Collection strains of M. avium, M. intracellulare, and Mycobacterium tuberculosis. Seven of 19 agents were selected for incorporation into liposomes. The MICs of these agents for 50 and 90% of isolates tested (MIC50s and MIC90s, respectively) ranged from 0.5 to 62 micrograms/ml. Members of the M. avium-M. intracellulare complex were resistant to killing by most of the other agents tested in the free form. However, clofazimine, resorcinomycin A, and PD 117558 showed complete killing of bacteria at concentrations ranging from 8 to 31 micrograms/ml, represented as MBC90s. Among the liposome-incorporated agents, clofazimine and resorcinomycin A had the highest killing effects (MBC90s, 8 and 16 micrograms/ml, respectively). Furthermore, both free and liposome-incorporated clofazimine had equivalent growth-inhibitory and killing effects on all American Type Culture Collection strains of M. avium, M. intracellulare, and M. tuberculosis tested. These results show that the antibacterial activities of certain drugs, particularly those of clofazimine and resorcinomycin, were maintained after the drugs were incorporated into liposomes.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Liposomes , Mycobacterium avium Complex/drug effects , Mycobacterium avium/drug effects , Cerulenin/pharmacology , Drug Carriers , Humans , Microbial Sensitivity Tests , Rifampin/pharmacologyABSTRACT
Hamycin has been used to treat a variety of yeast and other fungal infections by oral, topical, and intraperitoneal routes. However, its parenteral use has been reported to be associated with high toxicity. Multilamellar liposomes composed of dimyristoyl phosphatidyl choline, dimyristoyl phosphatidyl glycerol, and various amounts of cholesterol were used as drug carriers for hamycin. The antifungal activity of hamycin was maintained after liposome encapsulation (MIC range, 0.6-1.2 micrograms/ml), and toxicity was reduced in vitro and in vivo as the concentration of cholesterol was increased to an appropriate ratio. Mice were treated with various doses of free or liposomal hamycin 2 days after infection. Although free drug did not significantly improve survival, liposomal hamycin at an equivalent dose (0.6 mg/kg) increased the survival from 18 to 38 days. Higher doses (1.2 and 1.8 mg/kg) showed further improvement in survival and reduction in numbers of colony-forming units in the kidneys. Liposome encapsulation resulted in improved therapeutic index of hamycin.
Subject(s)
Antifungal Agents/pharmacology , Candida albicans/drug effects , Candidiasis/drug therapy , Animals , Antifungal Agents/administration & dosage , Antifungal Agents/toxicity , Cells, Cultured , Drug Carriers , Erythrocytes/drug effects , Erythrocytes/microbiology , Humans , Liposomes , Mice , Polyenes/administration & dosage , Polyenes/pharmacology , Polyenes/toxicityABSTRACT
HWA-138, a pentoxifylline analog, has been shown to increase yeast urinary clearance and to reduce yeast counts in the kidneys of rats infected with Candida albicans. Furthermore, HWA-138 has also been shown to prevent amphotericin B-induced acute renal failure in rats. We report here on the effects of HWA-138 alone and in combination with amphotericin B in the treatment of systemic candidiasis in mice. When single doses of HWA-138 were administered intravenously (10, 25, or 50 mg/kg of body weight) into infected mice, no significant improvement in survival was observed. In infected mice treated intravenously with multiple doses of HWA-138 (10, 25, or 50 mg/kg once daily for 5 consecutive days), a significant increase in survival time was seen only in animals also receiving 25 mg of HWA-138 per kg (14 +/- 3 days test versus 9 +/- 1 days control; P less than 0.05). The coadministration of subtherapeutic doses of amphotericin B and HWA-138 resulted in increased survival time. Combination therapy with amphotericin B (0.1-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) resulted in a significant increase in survival time over controls (19 +/- 4, 19 +/- 5, and 21 +/- 9 days, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P < 0.05). Variance analysis of these findings indicate synergistic activity between amphotericin B and HWA-138 in the treatment of experimental candidiasis in mice.
Subject(s)
Amphotericin B/therapeutic use , Antifungal Agents/therapeutic use , Candidiasis/drug therapy , Pentoxifylline/analogs & derivatives , Animals , Drug Synergism , Mice , Mice, Inbred ICR , Pentoxifylline/therapeutic useABSTRACT
The mechanism of amphotericin B (AmB) nephrotoxicity may be related to changes in vascular flow within the kidney, resulting in significant decreases in glomerular filtration rate and tubular integrity. The toxic and antifungal effects of AmB with and without the vascular decongestants pentoxifylline (PTX) and a methylxanthine analog, HWA-138, were compared in the murine model of candidiasis. At 48 h after inoculation with Candida albicans, half of the rats received a single intravenous 0.8 mg/kg dose of AmB whereas the others were administered sterile water. After 1 h, rats were randomized to receive three doses of 45 mg/kg PTX intraperitoneally, 5 mg/kg HWA-138 intravenously, or saline every 12 h. Renal function and Candida cell counts were estimated 24 h after AmB administration. Mean inulin clearances were significantly greater in rats coadministered AmB and PTX or HWA-138 than in AmB controls. Candida counts in kidneys of rats administered HWA-138 were similar independent of AmB therapy and markedly reduced compared with other groups. Whereas both vascular decongestants prevented drug-associated renal toxicity, the coadministration of AmB with HWA-138 resulted in a profound antifungal effect.
