Adriamycins

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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