Adriamycin

Adriamycin and 11-deoxyadriamycin when complexed to DNA cleave DNA in the presence of Fe3+ (Muindi et al. 1984). 

Tirapazamine (SR 4233) is the lead compound to a class of bioreductive anticancer drugs that makes use of the fact that solid tumors are hypoxic (Brown 1990, 1993 Brown and Wang 1998) and clinical phase III trials are under the way (Gandara et al. 2002). With an anticancer drug that is that far advanced in clinical trials one would like to know the mechanism of its action. Obviously, this has attracted many research teams that are expert in different techniques to tackle the problem. It will be shown below that there is now a host of first-class information, but it is as yet difficult, if not impossible, to arrive at a conclusive mechanism of its action. 

Neither the drug itself nor its two-electron reduction product SR 4317 are toxic as long as the cell is oxygenated [reactions (68) and (71)]. 

Under hypoxic conditions, cellular enzymes reduce the benzotriazine di-N-oxide [(reaction (68) P450 reductase Cahill and White 1990 and NADPH may be involved Walton et al. 1992 Wang et al. 1993]. Upon microsomal reduction of tirapazamine the radical formed in reaction (68) has been identified by EPR (Lloyd et al. 1991). Using the pulse radiolysis technique, it has been shown that this radical has a pKd of 6 (Laderoute et al. 1988), and it is the protonated form that undergoes the DNA damaging reaction (Wardman et al. 2003). The rate constants of the bimolecular decay of the radical [reaction (70)] has been found to be 2.7 x 107 dm3 mol-1 s 1. The reaction with its anion is somewhat faster (8.0 x 108 dm3 mol-1 s 1), while the deprotonated radicals do not react with one another at an appreciable rate. From another set of pulse radiolysis data, a first-order process has been extracted (k = 112 s 1) that has been attributed to the water elimination reaction (72), and the tirapazamine action on DNA [reaction (74)] has been considered to be due to the resulting radical (Anderson et al. 2003). 

Little if any base damage was detected using the 32P-postlabeling assay (Jones and Weinfeld 1996). Yet, this assay only records a limited number of such lesions 

Oxidation Damage by Bleomycin, Adriamycin and Other Cytotoxic Agents 

Because of the multiple facets to the chemistry of Adr, different sites and modes of action of the drug have been hypothesized. It can bind to DNA and may inhibit DNA replication after intercalation. The drug may undergo redox cycling in the presence of cellular reductants and Oj to generate oxy-radicals like the hydroxyl radical, which directly degrade DNA.  

Indeed, this mechanism might include direct binding of Fe to catalyze hydroxyl radical formation. Alternatively, the lipid solubility of Adr may direct it to the cellular membrane, where its capacity to undergo redox reactions and bind Fe may lead to lipid peroxidation and destruction of membrane analogous to its proposed effects on DNA.  

Besides proposed mechanisms that focus on oxidant-based damage to cells, the other hypothesized pathway of cytotoxicity with extensive support involves the inhibition of topoisomerase II (Topo II) by adriamycin. It is hypothesized that the inhibition of Topo II as it participates in DNA replication causes DNA double strand breakage. The nature of the interaction between Adr and Topo II has not been determined, nor has a link between cellular iron and inhibition of this enzyme been suggested. 

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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). 

Quinones of various degrees of complexity have antibiotic, antimicrobial, and anticancer activities, eg, a2iddinornitosene [80954-63-8] (36), (-)-2-methyl-l,4-naphthoquinone 2,3-epoxide [61840-91 -3] (37), and doxombicin [23214-92-8] (adriamycin) (38) (see Antibiotics Chemotherapeutics, anticancer), ah of these natural and synthetic materials have stimulated extensive research in synthetic chemistry. 

Cumulative organ toxicity also presents a significant obstacle for effective chemotherapy. In many cases, the severity of the toxicity impedes the broader use of an agent. Other specific toxicities are associated with specific agents, for example cardiotoxicity with adriamycin (32), renal toxicity with i7j -platinum (28), and neurotoxicity with vincristine (49). 

DOXORUBICIN see ADRIAMYCIN DRIERS, PAINT OR VARNISH, LIQUID, n.O.S. 

The piaximum concentration of the antibiotic was reached on the 6th day of fermentation. The quantity of adriamycin produced at this time corresponds to a concentration of 15... 

The antineoplastic antibiotics, unlike their anti-infection antibiotic relatives, do not have anti-infective (against infection) abilily. Their action is similar to the alkylating dragp. Antineoplastic antibiotics appear to interfere with DNA and RNA synthesis and therefore delay or inhibit cell division, including the reproducing ability of malignant cells. Examples of antineoplastic antibiotics include bleomycin (Blenoxane), doxorubicin (Adriamycin), and plicamycin (Mithracin). 

Lee et al. reported a novel and simple method for delivery of adriamycin using self-aggregates of deoxycholic acid modified chitosan. Deoxycholic acid was covalently conjugated to chitosan via a carbodiimide-mediated reaction generating self-aggregated chitosan nanoparticles. Adriamycin was... 

D Adriblastin (Pharmacia GB Caelyx (Schering-Plough USA Adriamycin (Pharmacia ... 

Strobel et al. (101) reported a unique approach to delivery of anticancer agents from lactide/glycolide polymers. The concept is based on the combination of misonidazole or adriamycin-releasing devices with radiation therapy or hyperthermia. Prototype devices consisted of orthodontic wire or sutures dip-coated with drug and polymeric excipient. The device was designed to be inserted through a catheter directly into a brain tumor. In vitro release studies showed the expected first-order release kinetics on the monolithic devices. 

Hyaluronic acid is a linear polysaccharide found in the highest concentrations in soft connective tissues where it fills an important structural role in the organization of the extracellular matrix (23,24). It has been used in ophthalmic preparations to enhance ocular absorption of timolol, a beta blocker used for the treatment of glaucoma (25), and in a viscoelastic tear formulation for conjunctivitis (26). The covalent binding of adriamycin and daunomycin to sodium hy-aluronate to produce water-soluble conjugates was recently reported (27). 

In a series of papers, Gupta et al. (109-112) studied the in vitro release properties of heat-stabilized BSA microspheres containing adriamycin. The biphasic release of drug was attributed to its location in the microsphere. The initial release results from surface desorption and diffusion through pores, while the later release arises from drug within the microsphere, which becomes available as the microsphere hydrates. 

Adriamycin release from BSA chemically crosslinked with tere-phthaloyl chloride was studied by Sawaya et al. (113). The unusual aspect of these studies is that incorporation was accomplished by immersing the crosslinked microspheres in a solution of the drug. 

Epirubicin, a successor to adriamycin, was studied in ovalbumin microspheres (115). The microspheres, prepared by a heat denatu-ration process, were 20 ym in diameter and contained 12.5% drug. 

Intraarterial infusion of microspheres containing adriamycin was used for the local treatment of breast cancer and recurrent breast cancer with liver metastases (123). A reduction in tumor size was noted when the microspheres were injected into the internal and lateral thoracic arteries for treatment of the primary tumor. However, hepatic artery injection for liver metastases resulted in improvement in only one of three patients treated. 

The release of adriamycin from BSA microspheres both with and without magnetic particles present as magnetite was investigated (137). While the presence of drug and/or magnetite had no effect on the size of the hydrated or unhydrated microspheres, the stabilization temperature affected the size of hydrated microspheres. 

Target tissue sections from animals sacrificed at 8 hr and later after dosing showed the presence of microspheres in the extravas-cular interstitial tissue. Changes in red blood cells and damage to other cellular components suggest that the cytotoxic properties of adriamycin have been retained. The microspheres appeared to still be intact for up to 72 hr. 

Prior to the study by Chen et al. (140), only one publication discussed the use of the protein casein as a drug carrier (141). Chen et al. systematically compared the many features of albumin and casein microspheres—morphology, drug (adriamycin) incorporation, and release—in an effort to identify important factors in the antitumor effect of this delivery system. 

In a similar study, adriamycin was incorporated into fibrinogen microspheres. In contrast to 5-FU, adriamycin released slowly from the matrix for up to 7 days, with little evidence of burst. This difference is probably attributable to the lack of surface release of adriamycin as evidenced by the unchanged nature of the microsphere surface. 

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