Disease relevance of Modane

• Based on these findings, we conclude that DHAQ produces a long-term (greater than 200 days) toxicity in rats that is not detectable by short-duration toxicity screening [1].
• A condition closely resembling human melanosis coli was induced in the guinea pig large intestine by daily oral administration of the anthraquinone danthron [2].
• The binding isotherms for the interaction of DHAQ with Clostridium perfringens DNA and poly(dA-dT).poly(dA-dT) exhibit a small positive slope at low r values, suggestive of cooperative binding [3].
• 1,4-Dihydroxy-5,8-bis[[2-(hydroxyethyl)amino]ethyl]amino-9,10-anthracenedione (DHAQ) was found to possess potent inhibitory activity against both the P-388 leukemia system (T/C of 299 at 0.5 mg/kg with 4/6 cures) and the B-16 melanoma system (T/C of 503 at 1 mg/kg with 7/10 cures) [4].
• At low r (bound drug/DNA base pair) values, r less than 0.03, DHAQ binds, in a highly cooperative manner, to calf thymus and Micrococcus lysodeikticus DNAs [3].

High impact information on Modane

• The two-electron reduction of these quinones by NAD(P)H-quinone oxidoreductase (DT-diaphorase) was not mutagenic, whereas the one-electron reduction, catalyzed by NADPH-cytochrome P-450 reductase, was mutagenic, except for danthron, which was only slightly mutagenic [5].
• Because danthron, though carcinogenic, does not seem to be genotoxic, it and 8 other hydroxyanthraquinones were comparatively investigated for activities associated with tumor promotion, such as stimulation of cell proliferation and enhancement of malignant transformation [6].
• DNA repair synthesis was elicited by several compounds of unknown carcinogenicity, 5,6- dimethoxysterigmatocystin , versicolorins A and B, averufin , xanthomegnin , luteosporin , and chrysazin , as well as by the carcinogenic myocotoxins , aflatoxin B1, sterigmatocystin, luteoskyrin , ochratoxin A, azaserine, mitomycin C, and actinomycin D [7].
• All animals that survived past Day 200 subsequently died by 1 year, displaying the same kinetics of lethality as those animals that had received DHAQ only [1].
• Comparison of the effects of dihydroxyanthraquinone and adriamycin on the survival of cultured Chinese hamster cells [8].

Chemical compound and disease context of Modane

• The effects of radiation combined with Adriamycin (ADR) or Dihydroxyanthraquinone (DHAQ, NSC 279836) on the induction of cardiomyopathy in the rat were investigated using electron microscopy [9].
• We had reported that the plant-derived 1,8-dihydroxyanthraquinone derivatives, emodin and danthron, were clearly genotoxic in mouse lymphoma L5178Y cells, whereas chrysophanol was only weakly genotoxic and physcion not at all [10].
• The effect of mitoxantrone (DHAQ) on [3H]thymidine and [3H]uridine incorporation by exponentially growing MDA-MB-231, a human breast tumor cell line has been studied [11].
• Because of an apparent typographic error in a US patent, there has been some confusion as to the acute oral toxicity of danthron and danthron in combination with dioctyl sodium sulfosuccinate (DSS) [12].

Biological context of Modane

• Dis as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage [13].
• Dis as revealed by cytogenetic assays; i.e., the drug with the highest therapeutic activity (DHAQ) was most active in inducing chromosome damage [13].
• The effect of dihydroxyanthraquinone (DHAQ), a potential anticancer chemotherapeutic agent, on the progression of Chinese hamster ovary cells into mitosis and on the division delay induced by ionizing radiation was studied using the mitotic selection procedure for cell cycle analysis [14].
• Action of dihydroxyanthraquinone on cell cycle progression and survival of a variety of cultured mammalian cells [15].
• DHAQ produced the greatest cytotoxicity in cells treated while in G1 or G2; ADR was more effective on cells located in S phase or mitosis [8].

Anatomical context of Modane

• Continued danthron administration caused progressive accumulation of pigmented macrophages in the bowel wall, whereas ongoing migration of pigmented macrophages to regional lymph nodes resulted, after danthron was ceased, in sequential loss of the pigmented cells from the superficial and deep lamina propria [2].
• PGE2 levels in the colorectal mucosa were significantly (P < 0.05 and 0.001) elevated after DHAQ treatment and showed some evidence of a dependence of DHAQ dose, consistent with the plasma PGE2 levels [16].
• The effects of 1,8-dihydroxyanthraquinone (DHAQ), a stimulant laxative named danthron, on cell kinetics and prostaglandin (PG) biosynthesis in the gastrointestinal tract were investigated in male 8-week-old F344 rats divided into three groups, each consisting of 10 animals [16].
• At autopsy performed 5 h after dosing, the highest percentage of the administered DHAQ was in the liver (49.7% +/- 2.7%), followed by the small intestine (7.1% +/- 0.7%), kidneys (2.7% +/- 0.1%), lung (1.9% +/- 0.3%), spleen (1.6% +/- 0.3%), and stomach (1.3% +/- 0.1%) [17].
• All of the effective mice (17) which were given 0.2% chrysazin diet and which survived more than 500 days developed adenomatous hyperplasia with cystic glands of the cecum [18].

Associations of Modane with other chemical compounds

• The clinical kinetics of 1, 4-dihydroxy-5,8-bis[[ 2-[(2-hydroxyethyl) amino] ethyl] amino]-9,10-anthracenedione dihydrochloride (DHAQ) are reported [19].
• Inhibition of DNA replication and repair by anthralin or danthron in cultured human cells [20].
• Enhancement of cell proliferation and prostaglandin biosynthesis by 1,8-dihydroxyanthraquinone in the rat large intestine [16].
• The equilibrium binding of the antitumor compound DHAQ, or mitoxantrone [1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10- anthracenedione], to various DNAs has been examined by optical titration and equilibrium dialysis methods [3].
• Rats were treated with ADR or DHAQ at 2.5, 5.0, or 10 mg/kg ip; thoracic irradiation at 12, 15, 18, 21, or 24 Gy of 25 MV X rays; or a combination of either drug at 5.0 mg/kg plus 15 Gy X rays [9].

Gene context of Modane

• In contrast, human lymphocyte viability was only mildly affected following 24 hr incubation with up to 5.0 micrograms dihydroxyanthraquinone per ml [15].
• The activity of ornithine decarboxylase of the colonic mucosa in mice exposed to chrysazin was stronger than that of animals without chrysazin [21].
• However, the inhibitory activity could not be attributed to the known stable oxidation product of anthralin, danthron, which did not decrease (12-LO activity [22].
• The mechanism of metal-mediated DNA damage by carcinogenic danthron (1,8-dihydroxyanthraquinone) and anthraquinone was investigated by the DNA sequencing technique using 32P-labeled human DNA fragments obtained from the human c-Ha-ras-1 protooncogene and the p53 tumor suppressor gene [23].
• Sequence-specific DNA damage induced by carcinogenic danthron and anthraquinone in the presence of Cu(II), cytochrome P450 reductase and NADPH [23].

Analytical, diagnostic and therapeutic context of Modane

• Electron microscopy of L1210 cells exposed a short time (90 min) to 0.21-21 microM DHAQ reveals segregation of nucleoli; the segregated granular portion shows increased electron opacity [24].
• A single injection of DHAQ (3 mg/kg i.p.) was equally uneffective up to 200 days after treatment (survival, greater than 90%) [1].
• Circular dichroism imaging microscopy: application to enantiomorphous twinning in biaxial crystals of 1,8-dihydroxyanthraquinone [25].
• The direct viral inactivation study demonstrated that HAQ, DHAQ, poly r(A-U) and the HAQ (or DHAQ)/poly r(A-U) combinations did not inactivate the VSV at concentrations near the viral 50% inhibitory dose [26].
• Studies on laxatives: biliary and urinary excretion in rats given danthron by intravenous infusion or gastric intubation [27].

References