Actinomycin daunorubicin

Polyalkylcyanoacrylate 0.2 Lysosomtropic after intravenous injection Antimitotics (e.g., daunorubicin, actinomycin D, doxorubicin)... 

Perhaps a bit more subtle than those agents that react chemically with DNA are those that insert themselves between the stacked bases of the DNA double helix— intercalation. This alters the regular structure of the DNA molecule and may lead, for instance, to inhibition of mRNA synthesis. The structures of the intercalcating agents are generally quite complex and I will spare you the complexity. However, three names may be familiar—dactinomycin (Actinomycin D), daunorubicin (daunomycin), and doxorubicin (Adriamycin)— and intercalation is how they work. All three are natural products and were isolated from the fermentation broths of Streptomyces species. 

A number of antibiotics possess pronounced cytostatic properties, and they are extremely effective in treating certain tumors. Included in this group are actinomycin, anthracyclins (daunorubicin and doxorubicin), bleomycin, and others. 

Acyclovir Erythromycin Ivermectin Itraconazole Rifampin Actinomycin D Daunorubicin Doxorubicin Docetaxel Epirubicin Etoposide Imatinib Irinotecan Paclitaxel Vinblastine Vincristine Amprenavir Indinavir Nelfinavir Ritonavir Saquinavir Cyclosporine A Tacrolimus Digoxin Quinidine Verapamil Diltiazem Aldosterone Cortisol Corticosterone Dexamethasone Hydrocortisone Cyclosporine Metkephamid Enkephalin... 

Fig. 3 Venn-diagram for selected compounds interacting with the key MDR-related ABC transporters. MDR-substrate anticancer agents. Abbreviations VCR vincristine, VP-16 etoposide, STER steroids, TAM tamoxiphen, TKI-INHIB tyrosin kinase inhibitors e.g. STI-571, DOX doxorubicine or adriamycin, DNR daunorubicin, EPIR epirubicin, MX mitoxantrone, TOPOT topotecan, iridotecan, BISANT bisanthrone, COLCH colchicin, ACT-D actinomycin D, MYTOM mytomycin, TX methotrexate, CPHAM cyclophosphamide, CHLB chlorambucil, CARM carmustine, LCV leucovorin, HUR hydroxy urea, CISPL cisplatin, TAXOL paclitaxel. (Reproduced from [4])...

Most of the important antitumor compounds used for chemotherapy of tumors are microbially-produced antibiotics. These include actinomycin D, mitomycin, bleomycins and the anthracyclines, daunorubicin and doxorubicin. The recent successful molecule, taxol (=paclitaxel), was discovered in plants but also is a fungal metabolite. It is approved for breast and ovarian cancer and is the only antitumor drug known to act by blocking depolymerization of microtubules. In addition, taxol promotes tubulin polymerization and inhibits rapidly dividing mammalian cancer cells. It also inhibits fungi such as Pythium, Phytopthora and Aphanomyces spp. by the same mechanism. ... 

Anthracyclines (SEDA-25, 533) aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin. Others acivicin, amsacrine, bleomycin, dactinomycin (actinomycin D), mitoxantrone. 

Crothers and coworkers (1.11) have also shown that the binding of ethidium to calf thymus DNA in the presence of dlstamycln (r(dlstamycln) = 0.037) is cooperative (J.), whereas the binding of ethidium in the absence of dlstamycln is non-cooperative. We report that the binding of daunorubicin to calf thymus DNA (r(daunorubicln) = 0.037) appears to alter the structure of the DNA as evidenced by tbe non-cooperative isotherm of actinomycin D. 

Figure 1. Chemical structure of (A) actinomycin D (key Thr, threonine Val, valine Pro, proline Sar, sarcosine and MeFal, methylvaline) (B) adriamycin and daunorubicin (C) DHAQ (D) NQO and (E) HAAF.

Actinomycin D dissociation kinetics were measured on a Cary 219 spectrophotometer equipped with a magnetic stirrer and thermostated cell holders. Sodium dodecyl sulfate (SDS) was used to sequester dissociating actinomycin D, and the resulting Increase In absorbance was monitored at 452 nm as a function of time. Stop-flow studies (daunorubicin and daunorubicin/ actinomycin D) were conducted with a Durrum-Glbson Model 110 stopped-flow spectrophotometer equipped with a dual detector accessory and a Tektronix storage oscilloscope Interfaced with a PDF 11/34 computer. Experiments were done In a 0.01M Na phosphate buffer, 0.1M NaCl, 0.001M NaEDTA, pH=7. Dissociation time constants were computed with a multlexponentlal analysis computer program. 

Figure 6. Scatchard plot for the binding of actinomycin D to calf thymus DNA daunorubicin complex.

The dissociation kinetics of daunorubicin and daunorubicin actinomycin D from poly(dAdT).poly(dAdT) were studied using stopped-flow techniques. The data is summarized in Table IV. The dissociation of daunorubicin from poly(dAdT).poly(dAdT) is monophaslc with a lifetime of 0.2 sec. In the ternary complex (daunorubicin actinomycin D poly(dAdT).poly(dAdT)) the dissociation of the daunorubicin is characterized by two exponential decays, yielding lifetimes of 0.2 sec and 5 sec, A single 5 sec dissociation time was observed for actinomycin D. 

This data is consistent with a model in which daunorubicin is bound to Isolated DNA binding sites and dissociates with its normal lifetime of 0.2 sec. Whereas daunorubicin and actinomycin D molecules, residing at "adjacent sites", dissociate with a time constant of approximately 5 sec. These results are indicative of a cooperative interaction between daunorubicin and actinomycin D when the two are bound to poly(dAdT).poly(dAdT). 

Anti-cancer drugs Actinomycin D, colchicine, daunorubicin, doxorubicin, etoposide, mitomycin C, paclitaxel,° vinblastine, vincristine "... 

Of the numerous anticancer drugs, eight have been reported to form free radicals, namely doxorubicin (= adriamydn = NSC-123127), daunorubicin (= daunomycin = NSC-83142), mitoxantrone (= NSC-301379), bleomycin (= NSC-125066), neocarzinos-tatin (= NSC-157365), mitomycin C (= NSC-26980), actinomycin D (= NSC-3053), and procarbazine (= NSC-77213). 

Wilson and Jones (1982) monitored the DNA P-NMR signal with addition of actinomycin D, ethidium, quinacrine, daunorubicin, and tetra-lysine. In each case it was found that the T", and NOE change negligibly with the addition, but the linewidth increased. Thus it was concluded that the internal motions in the backbone are unaffected by intercalation but that overall motion is diminished. 

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