Daunomycin toxicity

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Figure 5-23 Stereoscopic drawing showing a molecule of daunomycin (Fig. 5-22) intercalated between two base pairs in a molecule of double-helical DNA, d(CGTACG). Nitrogen and oxygen atoms are shown as dots. From Quigley et al.220 Both daunomycin and adriamycin (doxorubicin 14-hydroxy-daunomycin) are important but seriously toxic anticancer drugs.

A. Mukhopadhyay, B. Mukhopadhyay, R.K. Srivastava and S.K. Basu, Scavenger-receptor mediated delivery of daunomycin elicits selective toxicity towards neoplastic cells of macrophage lineage, Biochem. J. 284 (1992) 237-241. 

The superoxide formation is also responsible for the toxic action of daunomycin on the heart muscle. 

Human poison by ingestion. Experimental poison by subcutaneous, intravenous, and intraperitoneal routes. Experimental teratogenic and reproductive effects. Human mutation data reported. When heated to decomposition it emits toxic fumes of NOx. See also DAUNOMYCIN HYDROCHLORIDE. 

The antitumor activity of some derivatives of daunomycin at the amino and methyl ketone functions has been studied by Yamamoto etal. 43 Their studies were carried out mainly on leukemia 1210 in mice. At 2 mg/kg dose, the N-piperidinoimine derivative was found to have the same antitumor activity as daunomycin other derivatives were not active at this dose level. The N-acetyl derivative was found to posses only a little antitumor activity, but displayed no accute toxicity even at very high doses. According to our experience, the N-acetyl derivative was in most of the cases ineffective against tumor growth (Table 18). 

Hurwitz et al. (340) used a hydrazide derivative of poly(glutamic acid) as a carrier for daunomycin. This was less toxic than free drug against mouse lymphoma in vitro, but it was as effective, or more effective, against the same lymphoma in vivo. 

Anthracyclines - Adriamycin (ADR 20) has continued to be the dominant force in the expanding use of chemotherapeutic agents. Its wide spectrum of activity coupled with its dose-limiting cardiac toxicity continue to stimulate the search for structurally modified agents with improved biological profiles. Recent reviews on daunomycin (DNR 21),ADR and related antibiotics have appeared that discuss their chemistry and pharmacology. N-Trifluoroacetyladriamycin-14-valerate (AD-32 22), unlike the basic anthracyc lines, ADR and DNR, has been shown not to... 

Ionic rednction nsing a hydride occurs in vivo during the rednction catalyzed by NADH or NADPH enzymes, whereas one-electron rednction releases a radical structure, which may contribute to the toxic effect. Figure 33.13 illustrates the biotransformations affecting the anthracycline antitumor drug daunomycin. Recent stndies snggest that nitric oxide synthases may contribnte to the cardiotoxicity, probably becanse of their strnctnral similarities with CYP rednctase. ... 

Daunorubicin hydrochloride (daunomycin hydrochloride) is an anthracycline antibiotic that inhibits cellular proliferation by a variety of mechanisms, including DNA binding, free radical formation, membrane binding, and metal-ion chelation (49). A number of studies examining efficacy and toxicity in an animal model of PVR have been performed (50-56). Prior to 1998, experience with daunorubicin in human trials was more limited (57-59). 

Wiedemann P, Heimann K. Toxicity of intraocular daunomycin. Lens Eye Toxic Res 1990 7 305-310. 

Santana M, Wiedemann P, Kirmani M, et al. Daunomycin in the treatment of experimental proliferative vitreoretinopathy retinal toxicity of intravitreal daunomycin in the rabbit. Graefes Arch Clin Exp Ophthalmol 1984 221 210-213. 

Steinhorst UH, Hatchell DL, Chen EP, Machemer R. Ocular toxicity of daunomycin effects of subdivided doses on the rabbit retina after vitreous gas compression. Graefes Arch Clin Exp Ophthalmol 1993 231 591-594. 

The most basic structural model for anthracyclines adriamycin (doxorubicin) and daunomycin (daunorubicin) was considered to be tiie strongly intramolecularly hydrogen-bonded naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) (Section 3.2). It is usually customary to study the way in which such simple quinones form radicals in order to gain insight into the way more complex quinones might produce toxic and other effects. This is more so as the radical centres in the complex molecules are usually located in these simpler model structures. Treatment of naphthazarin will also demonstrate how various data may be compiled and compared. 

RA-V is the same compound as deoxybouvardin (151). Bouvardin (165) has been investigated for development as an antitumor drug at the U.S. NCI. Adryamycin has CH2OH instead of CH3 as in daunomycin. With such minor chemical differences, adryamycin was revealed to have a much stronger activity and less toxicity than daunomycin. Therefore, it is expected that RA-VII will show different activity from that of bouvardin. RA-VII (RA-700) was under investigation for phase I clinical trials at the NCI in Japan. 

Rihova B, Kopeckova P, Strohalm J, Rossmann P, Vetvicka V, Kopecek J. Antibody directed affinity therapy applied to the immune system in vivo effectiveness and limited toxicity of daunomycin conjugates to HPMA copolymers and targeting antibody. Clin Immunol Immunopathol 1988 46 100-114. 

Since Brockman s discovery of toxic pigments produced by Streptomyces in the early 1960s [8], thousands of new daunomycin derivatives have been obtained, either by synthesis involving glycosidic bond reassembly or by directed biogenesis. Early discussions on structure-activity relationships are presented in a fundamental account elaborated by Arcamone [3,92]. Over the years, as the methods for evaluation of drug candidates became more so-... 

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