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Anthracyclines: Anti-Cancer Compounds

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Daunorubicin HCl

Biochemicals > Anticancer

Substance Name:NDC 0082-4155; Ondena; RP 13057

CAS Number:23541-50-6

As low as $ 110.00
Price $ 110.00
10 MG $ 110.00
50 MG $ 245.00

Doxorubicin Hydrochloride

Antibiotics > Antibiotics (D)

Substance Name:Doxorubicin HCl; DOX

CAS Number:25316-40-9

As low as $ 75.00
Price $ 75.00
10 MG $ 75.00
50 MG $ 161.50

Epirubicin Hydrochloride

Antibiotics > Antibiotics (E - G)

Substance Name:4’-Epidoxorubicin

CAS Number:56390-09-1

As low as $ 95.00
Price $ 95.00
5 MG $ 95.00
25 MG $ 250.00

Anthracyclines are anticancer compounds that were originally derived from Streptomyces and their anti-tumor activitieswere established in the 1960s. Anthracyclines are red aromatic polyketides and occur in variety of forms due to the structural differences in the aglycone and the different sugar residues attached.

Anthracyclines are anti-cancer compounds that were originally derived from Streptomyces and their anti-tumor activities were established in the 1960s. Anthracyclines are red aromatic polyketides and occur in variety of forms due to the structural differences in the aglycone and the different sugar residues attached.

Major Anthracycline Drugs

    • Daunorubicin (Daunomycin): was the first anthracycline compound to be characterized structurally and stereochemically. Danorubicin is used in treating acute lymphoblastic and myeloblastic leukaemias.
    • Doxorubicin (Adriamycin): is a hydroxyl derivative of daunorubicin. Doxorubicin is one of the most widely used chemotherapeutic agents and is generally prescribed in combination with other drugs. Doxorubicin has a broad spectrum of activity. It is one of the most effective drugs for solid tumor treatment, such as breast cancer, small cell lung cancer and ovarian carcinoma treatments. It has significant activity against bladder, stomach, liver and thyroid tumors, Ewings and osteogenic bone tumors, soft tissue sarcoma, neuroblastoma and Wilms tumors. It is also active against multiple myelomas, several types of leukaemia and cutaeneous T-cell lymphoma. It also plays an important role in the treatment of Hodgkins disease and non-Hodgkins lymphomas.
  anthracycline antibiotics Due to development of resistance in the tumor cells to daunorubicin and doxorubicin, dose dependent cardiotoxicity, and several other side-effects, modification of these drugs to produce analogs with wider activity and lower toxicity have been sought. Efforts to find better anthracyclines over the years has increased the number of analogs to more than 2,000. However, only very few anthracycline analogs like epirubicin and idarubicin have been approved for clinical use.
    • Epirubicin: Epirubicin is an epimer of doxorubicin and differs only in the orientation of the C-4 hydroxyl group on the sugar. Because of this slight change in the structure, epirubicin has lower cardiotoxicity than doxorubicin. Epirubicin is used in the treatment of gastric and breast cancer and is also indicated for the treatment of carcinoid, endometrial, lung, ovarian, esophageal and prostate cancers as well as soft tissue sarcomas.
    • Idarubicin: Idarubicin is an analog of daunorubicin. It lacks the C-4 methoxy group and this increases its lipophilicity. Idarubicin has improved activity as induction therapy for acute myelogenous leukaemia.
  • Valrubicin: Valrubicin is N-trifluoroacetyl, 1-4-valerate derivative of doxorubicin. Valrubicins enters cells more rapidly than doxorubicin. It is used specifically in the treatment of early bladder cancer.

Mechanism of action

The mechanism by which anthracyclines inhibit cancer is still not completely clear and multiple pathways are thought to be involved in the cytotoxicity of this class of anti-cancer drugs. The useful pathways are the ones that are actually involved in toxicity to the neoplasia while not being toxic to the organism. Beakers

Accumulation of anthracyclines in the nucleus of neoplastic and proliferating cells

Anthracyclines enter the cells through passive diffusion. An elegant mechanism of the selective transport of anthracyclines to the nuclei of neoplastic and proliferating cells has been proposed by Kiyomiya and colleagues. It has been demonstrated with doxorubicin that once it enters the cells, it binds the proteasomes in the cytoplasm for which it has high affinity. The drug-proteasome complex is then translocated into the nucleus. Proteasomes are shown to be located predominantly in the nucleus of neoplastic and normal proliferative cells as compared to the non-proliferative normal cells that show the presence of proteasomes predominantly in the cytoplasm. Thus there will be a relatively higher transport of anthracyclines into the nucleus of the neoplastic and non-differentiated, proliferative normal cells. Once the anthracyclines reach the nucleus they would dissociate from the proteasome and bind DNA due to its higher affinity for DNA. This would bring about the DNA mediated effects of anthracyclines. Moreover, binding of anthracyclines to proteasomes also inhibits the protease activity leading to inhibition of degradation of proteins involved in cell growth and metabolism and thus inducing apoptosis of these cells.

DNA intercalation

Intercalation into DNA leading to inhibition of macromolecular synthesis was the first mechanism described for cytotoxicity of anthracyclines. The rather strong binding of daunorubicin and doxorubicin to DNA has been characterized extensively. However, it has been seen with other anthracyclines like those of the nogalamycin family that the anti-tumor activity correlates with a decrease in affinity for DNA. Considering this and also taking into account that the DNA in cells does not occur naked but as chromatin, it seems unlikely that DNA intercalation is the only or most essential pathway of anthracycline cytotoxicity. On the other hand, anthracyclines like doxorubicin at low concentrations have been shown to selectively displace nuclear proteins, and daunorubicin has been shown to induce aggregation of chromatin. The proposed mechanism involves initial intercalation of the drug into the linker regions where the DNA is free of nuclear proteins, leading to conformational changes in DNA that extend towards the histone octamer and result in the unfolding of chromatin and its subsequent aggregation.

Interaction with DNA binding proteins

Regulation of gene expression by inhibiting or promoting the binding of transcription factors is also considered to play a role in anthracycline cytotoxicity with the potential involvement of SP-1 transcription factor as a specific target for these drugs. Involvement of anthracyclines in inhibiting DNA synthesis by affecting the initiation or the elongation phase, and RNA synthesis by inhibiting RNA polymerase activity has also been documented. Another mechanism that has gained ground is the anthracycline activity as topoisomerase II poisons. After DNA intercalation, anthracycline rings that do not intercalate into the DNA seem to play a role in stabilizing the complex between topoisomerase II and the DNA that it has nicked. The DNA nicks cannot be sealed and this leads to an accumulation of DNA damage that is cytotoxic due to growth arrest in G1 and G2 and programmed cell death. Doxorubicin and idarubicin have also been showed to inhibit topoisomerase I and this is proposed to be an ancillary mechanism of cytotoxic activity of anthracyclines.

Anthracyclines, p53 and apoptosis

Like any other genotoxic agent, doxorubicin has been demonstrated to induce the binding of p53 to DNA. As p53 is a major player in some forms of apoptosis, it has been proposed that anthracyclines may exert their cytotoxic effect via p53 mediated apoptosis. There are contradictory reports regarding this link between anthracyclines, p53 and apoptosis. It is observed that there are more DNA breaks in p53 proficient cells than in p53 deficient cells although the levels of topoisomerase II are same in the two cell types. It is therefore also proposed that p53 exerts this activity by binding to topoisomerase II and inhibiting its ligase activity. However, clinical concentrations of these drugs induce apoptosis pathways that do not always require p53 by triggering a cyclic cascade of sphingomyelin hydrolysis and formation of ceramide. It is also observed that anthracyclines can release cytochrome C from mitochondria directly and induce apoptosis. Thus, although p53 seems to play some role in the activity of anthracyclines, it is not necessarily the only mechanism.