Doxorubicins

The chief toxicity associated with vinblastine use is bone marrow depression. The toxicity of vincristine consists of paresthesia, neuritic pain, muscle weakness, and visual disturbances. In addition, both vinblastine and vincristine may cause alopecia. 

The antibiotics that bind to DNA are nonspecific to the cell-cycle phase. Dactinomycin (actinomycin D and Cosmegen) binds to double-stranded DNA and prevents RNA synthesis by inhibiting DNA-dependent RNA polymerase. It is administered intravenously in the treatment of pediatric solid tumors such as Wilms tumor and rhabdomyosarcoma and for gestational choriocarcinoma. Dactinomycin causes skin reactions, gastrointestinal injury, and delayed bone marrow depression. 

The mechanism of action of mithramycin (Mithracin) is similar to that of dactinomycin. It is used in patients with advanced disseminated tumors of the testis and for the treatment of hypercalcemia associated with cancer. Mithramycin may cause gastrointestinal injury, bone marrow depression, hepatic and renal damage, and hemorrhagic tendency (see Chapter 62). 

Daunorubicin (Daunomycin and Cerubidine) and doxorubicin (Adriamycin) bind to and cause the intercalation of the DNA molecule, thereby inhibiting DNA template function. They also provoke DNA chain scission and chromosomal damage. Daunorubicin is useful in treating patients with acute lymphocytic or acute granulocytic leukemia. Adriamycin is useful in cases of solid tumors such as sarcoma, metastatic breast cancer, and thyroid cancer. These agents cause stomatitis, alopecia, myelosuppression, and cardiac abnormalities ranging from arrhythmias to cardiomyopathy. 

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

Bisantrene (56), also known as orange crush", is a broad spectrum intercalating antitumor agent competing with doxorubicin and the somewhat more closely related quinone mitoxantrone (51)... 

Streptomyces peucetius var. caesius Doxorubicin Streptomyces rimosus Oxytetracycline Streptomyces rimosus forma paromomycinus Paromomycin... 

P-gp (ABCB1) Verapamil, digoxin, mitoxantrone, vinblastine, doxorubicin, losartan, talinolol, cortisol, dexamethasone, colchicine, loperamide, domperidone, indinavir, erythromycin, tetracycline, itraconazole, cyclosporine, methotrexate, amitryptyline, phenobarbital, morphine, cimetidine, and others... 

MRP1 (ABCC1) Glucuronides and sulfate conjugates of steroid hormones and bile salts, colchicine, doxorubicin, daunorubicin, epirubicin, folate, irinotecan, methotrexate, pacitaxel, vinblastine, vincristine, and others... 

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). 

EPI, epimbicin DOX, doxorubicin ROS, reactive oxygen species DNR, daunorubicin... 

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). 

MANAGING ALOPECIA. Alopecia (loss of hair) is a common adverse reaction associated with some of the antineoplastic drugs. Some drugs cause severe hair loss, whereas others cause gradual thinning. Examples of drug commonly associated with severe hair loss are doxorubicin and vinblastine Methotrexate, bleomycin, vincristine, and etoposide are associated with gradual hair loss. 

DOX, doxorubicine TAX, taxol MTX, methotrexate DDPt, cisplatin 5PU, flurouracil ETO, etoposide. 

The differential diagnosis for PIH includes the following fixed drug eruption, systemic drug-induced hyperpigmentation, macular amyloid, ashy dermatosis, melasma, and tinea versicolor. Medications such as tetracyclines, antimalarial drugs, arsenic, bleomycin, and doxorubicin can result in hyperpigmentation of the skin. 

Juni, K., Ogata, J., Nakano, M., Ichihara, T., Mori, K., and Akagi, M., Preparation and evaluation in vitro and in vivo of polylactic acid microspheres containing doxorubicin, Chem. Pharm. Bull.. 33, 313, 1985. 

The tumoricidal activity of MRAMs containing either doxorubicin or protein A, a constituent of the cell wall of Staphylococcus aureus, was tested in rats with induced mammary adenocarcinoma (138). 

Apart from the passive encapsulation methods, different active entrapment techniques are described in the literature. Nichols and Deamer (1976) prepared liposomes with a pH gradient across the membrane (acidic interior with respect to the external buffer). These liposomes efficiently incorporated several catecholamines added to the external buffer. The same technique has been used to concentrate doxorubicin (DXR) in pH gradient liposomes (Mayer et al., 1986b). 

The same group also demonstrated that doxorubicin and vinblastine can be rapidly accumulated into egg-PC LUV in response to a valino-mycin-dependent K" " diffusion potential (Mayer et al., 1985b). 

Because of its clinical importance and the expected benefits of the drug in liposomal form for cancer treatment, all three American "liposome enterprises" (i.e.. Liposome Technology Inc., Erbamont, LyphoMed/Vestar joint ventures, and the Liposome Company, Inc.) are developing a formulation of liposomal doxorubicin. Clinical studies already show promising results as far as the acute toxicity is concerned (less vomiting, nausea, and hair loss) (Gabizon et al., 1989 Treat et al., 1989),... 

Gabizon A., Sulkes, A., Peretz, T., Druckmann, S., Goren, D., Amselem, S., and Barenholz, Y. (1989). Liposome-associated doxorubicin Preclinical pharmacology and exploratory clinical phase, in Liposomes in the Therapy of Infectious Diseases and Cancer. (G. Lopez-Berestein and I. J. Fidler, eds.), Alan R. 

Storm, G. (1987). In Liposomes as Delivery System for Doxorubicin in Cancer Chemotherapy. (Ph.D. Thesis.) University of Utrecht, The Netherlands. 

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