Antibiotics, anthracycline, binding

Doxorubicin is an antineoplastic/anthracycline antibiotic. It binds DNA and inhibits nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations. It is indicated in treatment of ovarian cancer in patients whose disease has progressed or recurred after platinum-based chemotherapy and in treatment of AIDS-related Kaposi s sarcoma in patients whose disease has progressed on prior combination chemotherapy or who are intolerant to such therapy. 

Anthracyclines are antitumor quinone containing antibiotics produced by different strains of Streptomyces. Some of them, such as adriamycin doxorubicin), and daunorubicin are broad spectrum antitumor compounds. They act by binding to DNA and interfering with DNA replication and gene transcription. Their limitations for clinical use are cardiac toxicity and drug resistance phenomena. Consequently, intense structure-activity relationship studies have been performed to improve the pharmacological profile as well as to enhance the affinity for DNA. In particular, a number of fluorinated anthracyclines have been prepared with introduction of fluorine atoms into D or A cycles, and into the aglycone side chain linked atC-14. ... 

Reactive derivatives of anthracycline antibiotics were synthesized and attached to polymeric carriers. To bind adriamycin to poly(glutamic acid) and poly(aspartic acid) via ester bonds, Zunino et al. [147] used the reaction of alkylbromides (14-bromodaunorubicin) with the carboxylic group of the carrier. 

Screening of microbial products has led to the discovery of a number of growth-inhibiting compounds that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both cause DNA strand scission and interfere with cell replication. All of the anticancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Streptomyces. These include the anthracyclines, bleomycin, and mitomycin. 

Daunomycin and adriamycin bind to DNA with similar binding constants of t.2.5 x 10 M- in 0.1 M buffer, pH 7.0 at 20°C, with one anthracycline antibiotic bound per six nucleotides at maximum intercalative binding (80,81). The binding constant is dependent on the salt concentration and decreases by a factor of 5 on proceeding from 0.1 M to 1.0 M NaCl solution (82). 

The results obtained by various workers employing these several techniques are not in total agreement. It seems clear, however, that the presence of deoxyguanosine residues in DNA is required for binding of Actino-mycin D. Anthracyclines can complex with poly dAT and poly dGdC however, binding of nogalamycin may be favored by dAT pairs while that of daunomycin is not. The presence of cations (Mg" or Cs" ) may play a role in complex formation between the chromomycin antibiotics and DNA. 

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). 

More recently, research indicates that the anthracycline compounds have an inhibitory effect on the intracellular enzyme topoisomerase II (also see Chapter 7). This has been taken as evidence that this enzyme may be the primary target for these drugs. A more balanced view at this time may be that the carcinolytic mechanism of action of the anthracycline antibiotics is related to the binding affinity to DNA (intercalation), inhibition of nucleic acid synthesis, and topoisomerase II interactions. 

Other Poisson-Boltzmann binding studies have come to the same conclusions. A number of interesting results are referenced involving studies of MHC class 1 protein-peptide, homeodomain-DNA, and anthracycline antibiotics-DNA interactions and the interested reader is directed to follow these for more information.107-109... 

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