Anthracycline doxorubicin

The anthracyclines represent a broad family of antibiotics that exhibit activity in numerous tumors. The first anthracyclines, doxorubicin (DOX) and dau-notubicin (DNR), were isolated from Streptomyces var peucetius they were shown to be composed of a tetracyclic ring system with adjacent quinone-hydro-quinone moieties, a short side chain with a carbonyl group, and an aminosugar bound to the C-7 of the four-ring system. DOX and DNR only differed in the side chain terminus (-CH2OH in DOX vs. -CH3 in DNR). Second generation anthracyclines, like epitubicin (EPI) and idatubicin (IDA), were obtained after minor chemical modifications of DOX or DNR, respectively (Fig- 1). 

Anthracyclines Doxorubicin, epirubicin Myelosuppression, cardiomyopathy Alopecia, nausea, vomiting, stomatitis, ulceration necrosis with extravasation, red-colored urine, radiation-recall effect... 

Anthracyclines Doxorubicin/ adriamycin Melanoma, Ovarian carcinoma, T-cell lymphoma, Colon carcinoma, B-cell lymphoma, Various disseminated refractory malignandes, Breast cancer, Lung cancer, Pancreatic cancer, Liver cancer, Neuroblastoma... 

The kinetics of removal of iron(III) from its complexes with the aminocarboxylate-anthraquinone analytical reagent calcein and with the antitumor anthracycline doxorubicin by l,2-dimethyl-3-hydroxy-4-pyridinone (LI, (251) with R = R = Me) have been monitored. Rate constants for metal removal are almost independent of the concentration of the replacing ligand, indicating dissociative mechanisms they are approximately 1 x 10 s for displacement from doxorubin and between 12 x 10 s and 2 x 10 s from calcein. 

A total of 469 patients were enrolled into a randomized, multicenter, phase III trial of chemotherapy with or without Herceptin [52]. All patients had previously untreated, IHC 2+/3+ MBC. Patients who had previously received anthracyclines in the adjuvant setting were randomized to receive paclitaxel (175 mg m 3-weekly) alone (n=96) or with Herceptin (n=92). All other patients were randomized to receive anthracycline (doxorubicin 60 mg m or epirubicin 75 mg m ) plus cyclophosphamide (600 mg m ) alone (n=138) or with Herceptin (n=143) (Fig. 5.7). The primary endpoint was TTP. Secondary endpoints were ORR, DR, TTF, OS and 1-year survival. An independent RFC determined disease progression and response. 

The anthracyclines have been by far the most studied of all cardiotoxic drugs and doxorubicin is by far the most studied of the anthracyclines. Doxorubicin is a microbial derived natural product that has proven clinical acdvity in a wide array of tumors. The mechanism of acdon ascribed to this drug is the inhibition of topo-isomerase 11 following DNA intercalation, thus interfering with cell division. Not surprisingly this drug causes reversible marrow suppression and G1 disturbances. However, once entered into the clinic a disturbing pattern of cardiotoxicity was observed in cancer patients. 

Scheme 1 Structures of anthracyclines doxorubicin, nogalamycin, aclacinomycin A, P-rho-domycin, cosmomycin D, steffimycin and aranciamycin...

Among all ABC transporters, P-gp, also known as MDRl protein, ABCBl or CD243, is probably the most studied and characterized member. It was first found as a 170-kDa ATP-dependent membrane glycoprotein that acts as a drug efflux pump [15], P-gp is a broad-spectrum transporter, capable of transporting several structurally and functionally unrelated substrate molecules. Its substrates are typically hydrophobic, amphipathic products, including many chemotherapeutic compounds used for cancer treatment, e.g., vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel, docetaxel), epipodophyllotoxins (etoposide, teniposide), anthracyclines (doxorubicin, daunorubicin, epirubicin), topotecan, dactinomycin, and mitomycin-C [37]. 

Doxorubicin and other anthracyclines, such as daunorubicin, are believed to exhibit their antineoplastic activity through inhibition of topoisomerase II activity. This appears to occur in the absence of significant metal binding by the anthracyclines. Doxorubicin can, however, bind with iron(III) and this results in the formation of a redox-active complex that may cause untoward effects (Myers et al. 1986). Doxorubicin-iron(III) complexes have been shown to oxidatively damage membranes and inactivate protein kinase C, but the biological signficance of this is not well understood (Hannun et al. 1989). 

Anthracyclines, doxorubicin, daunomycin and idarubicin, belong to the most widely used anticancer agents and many efforts have been made in order to remove their undesirable side effects. Recently, convenient syntheses of daunomycinone-7-D-glucuronides and doxorubicinone-7-D-glucuronides have been reported by Rho et who fully characterised their anomeric configuration and conformation by the assignment of H NMR chemical shifts and H-H couplings. 

Cardiovascular Heart failure (New York Heart Association classes II-IV) has been observed in patients receiving trastuzumab, alone or in combination with paclitaxel or docetaxel, particularly after chemotherapy containing an anthracycline (doxorubicin or epirubicin) [303, 304, 305, 306. It can be moderate or severe and can be fatal. The results of many randomized trials have shown that the degree of cardiotoxicity is generally acceptable the incidence of cardiac damage caused by trastuzumab was 0.4-4.1% [307 ]. Older age, lower left ventricular ejection fraction, and antihypertensive medications are associated with an increased risk of cardiac dysfunction in patients receiving trastuzumab [308 "]. The cardiac dysfunction associated with trastuzumab is usually reversible on withdrawal and standard medical therapy [309 ]. In one case, trastuzumab-associated cardiomyopathy presented with complete left bundle-branch block mimicking acute coronary syndrome [310" ]. 

The DNA-binding properties of anthraquinones have been studied intensively over the past 25 years because of their clinical potential as anticancer drugs. The anthraquinone system is often found in anti-tumor drugs such as anthracyclines, mitoxantrone (11a), ametantrone (11b) and derivatives thereof [217-220]. Mitoxantrone (11a) and ametantrone (11b) have attracted much interest because of their lower risks of cardiotoxic effects compared with the naturally occurring anthracyclines doxorubicine (adriamycin) (4b) and daunorubicin [221]. 

Anthracyclines. - Doxorubicin (DOX) and daunorubicin (DNR) are amongst the most frequently prescribed anticancer agents, but the mechanisms underlying their activity are not well understood. However, the ability of an-... 

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