Disease relevance of Miracil D

• Clinical trials were undertaken to determine whether lucanthone (miracil D) affects radiation-induced regression in measurable pulmonary metastases and advanced squamous-cell oral and pharyngeal tumors [1].
• Lucanthone modification of cyclophosphamide toxicity in the Chinese hamster [2].
• Five methylthioxanthenone and methylbenzothiopyranoindazole analogues, including lucanthone (Miracil D), are non-mutagenic for Salmonella typhimurium but are activated to mutagens by a rat liver microsome preparation [3].
• 18-h urine samples collected from male CD-1 mice which had been treated with either 2-aminofluorene, cyclophosphamide, or lucanthone were incubated with beta-glucuronidase, then added directly to cultures of L5178Y TK+/- mouse lymphoma cells for 3 h [4].
• Inhibition of the human apurinic/apyrimidinic endonuclease (APE1) repair activity and sensitization of breast cancer cells to DNA alkylating agents with lucanthone [5].

High impact information on Miracil D

• A sublethal dose of 100 mg lucanthone hydrochioride/kg (Miracil D, Nilodin; NSC-14574) administered ip into Chinese hamsters [median lethal dose for 30-day survival (LD50/30) of 315 mg/kg] reduced the radiation tolerance of the small intestine and had little or no effect on the radiation tolerance of the bone marrow [6].
• The LD50/30, indicative of death from bone marrow stem cell depletion, remained unaltered at approximately 990 rads over the entire treatment scheme, which indicated that the radioresponsiveness of bone marrow stem cells was unaffected by lucanthone hydrochloride [6].
• Exposure of HeLa cells to lucanthone (3 microgram/ml) caused dissociation of a fast-sedimenting duplex DNA complex, as judged by lysis and sedimentation in alkaline sucrose gradients [7].
• The data obtained suggest that the reduced synthesis of rRNA in lucanthone-treated eukaryotic cells is due to lack of reinitiating RNA polymerases possibly caused by improper termination [8].
• Effect of lucanthone (miracil D) on transcription of ribosomal RNA genes from Tetrahymena in vivo and in vitro [8].

Biological context of Miracil D

• The median lethal dose for 7-day survival (LD50/7), indicative of death from gastrointestinal epithelial denudation, was reduced from 1,235 rads to minimum values of 995 rads or 985 rads by lucanthone hydrochloride inoculation 10 hours before irradiation or 7.5 hours post irradiation, respectively [6].
• Using a radiolabelled linear plasmid DNA as a substrate, both lucanthone and the indazole analogue were shown to promote the cleavage of DNA by human topoisomerase II [9].
• At no time was the D0 of the crypt cell survival curve affected by lucanthone [10].
• From the observation that hycanthone- and lucanthone-induced mutations exhibited different germ-cell-stage sensitivity patterns, it was concluded that lucanthone does not (at least not exclusively) act via metabolic activation to hycanthone [11].
• None of the compounds tested stimulated the activity of ribonuclease T1, and only chloroquine, and perhaps lucanthone, stimulated the hydrolysis of tRNA by ribonuclease N1 [12].

Anatomical context of Miracil D

• Effects of lucanthone on the sedimentation properties of DNA from HeLa cells [7].
• Lucanthone, therefore, readily crossed the blood-brain barrier in experimental animals [13].
• The LD50/30 for CYC was only slightly reduced by the presence of lucanthone, indicating that bone marrow sensitivity to CYC was only marginally affected by lucanthone [2].
• Lucanthone as a radiosensitizing agent in the treatment of carcinoma of the cervix [14].
• Effects of the schistosomicide 1,7-bis(p-aminophenoxy)heptane (153C51) on lysosomes and membrane stability [15].

Associations of Miracil D with other chemical compounds

• Proceedings: Interaction of tetracycline and lucanthone on radiation damage in mammalian embryos as dependent on LET (experiments with pions) [16].
• When these same chemicals were tested directly as mutagens in L5178Y TK+/- cells, lucanthone and, to a lesser extent, cyclophosphamide were positive both with or without metabolic activation; and aminofluorene was only positive with activation [4].
• Recovery of the hepatic drug-metabolizing capacity in mice infected with Schistosoma mansoni following curative chemotherapy with the schistosomicide 4-isothiocyano-4'-nitro-diphenylamine (CGP 4540) [17].
• Oxamniquine is a potent schistosomicide used clinically in the treatment of infections due to Schistosoma mansoni [18].

Gene context of Miracil D

• The ability of lucanthone to inhibit the normal repair of abasic sites might reflect inhibition of apurinic/apyrimidinic endonuclease (HAP1) by the drug, thereby preventing an early step in the base excision repair pathway [19].
• Butyrylcholinesterase inhibition by miracil D and other compounds [20].
• Pretreatment of human leukemia THP-1 cells with heat shock protein Hsp70 (Hsp70) protected them from the cell-lethal effects of the topoisomerase II inhibitor, lucanthone and from ionizing radiation [21].
• Given these initial findings, it would be of interest to further develop lucanthone as an APE1 inhibitor through the use of structure-function studies as a means of enhancing the sensitization of tumors to chemotherapeutic agents [5].
• We report that lucanthone inhibits the repair activity of APE1, but not its redox function or exonuclease activity on mismatched nucleotides [5].

Analytical, diagnostic and therapeutic context of Miracil D

• Size determinations were made of patients' brain metastases from magnetic resonance images or by computed tomography before and after treatment with 30 Gy whole brain radiation alone or with lucanthone [13].
• METHODS AND MATERIALS: Lucanthone was incubated with human topoisomerases II and I together with their plasmid substrates, to determine if lucanthone interfered with the catalytic activities of topoisomerases and if it enhanced the formation of DNA strand breaks, as determined by agarose gel electrophoresis of the resultant plasmid forms [22].
• Schistosomicide drugs are used as ligands to isolate the target antigens of schistosome by affinity chromatography [23].
• Worm recovery by perfusion of the porto-mesenteric system, followed by counting and a morphometric study of the parasite, allowed the conclusion that the relative resistance of the larval stages of S. mansoni to schistosomicide drugs, demonstrated in primary infections, also persists when the host is already infected [24].
• The application of a known radiosensitizer (lucanthone) combined with 13.5 rd whole-body irradiation on day 8 of gestation showed enhanced teratogenic action compared to treatment with each of the agents alone [25].

References