Bisantrene
Identifiers
  • N-[(E)-[10-[(E)-(4,5-dihydro-1H-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1H-imidazol-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC22H22N8
Molar mass398.474 g·mol−1
3D model (JSmol)
  • C(=NNC1=NCCN1)c1c2ccccc2c(C=NNC2=NCCN2)c2ccccc12
  • InChI=1S/C22H22N8/c1-2-6-16-15(5-1)19(13-27-29-21-23-9-10-24-21)17-7-3-4-8-18(17)20(16)14-28-30-22-25-11-12-26-22/h1-8,13-14H,9-12H2,(H2,23,24,29)(H2,25,26,30)
  • Key:NJSMWLQOCQIOPE-UHFFFAOYSA-N

Bisantrene, trademarked as Zantrène, is an anthracenyl bishydrazone with anthracycline-like antineoplastic activity and an antimetabolite.[1] Bisantrene intercalates with and disrupts the configuration of DNA, resulting in DNA single-strand breaks, DNA-protein crosslinking, and inhibition of DNA replication. This agent is similar to doxorubicin in activity, but unlike anthracyclines like doxorubicin, exhibits little cardiotoxicity.[2]

Bisantrene has been identified a potent (IC50 142nM) Fat Mass and Obesity (FTO) associated protein a m6A RNA demethylase.[3]

Bisantrene is undergoing Phase II trials to assess its efficacy to target cancers and side effects.

Medical uses

Clinical trials of Bisantrene in the 1980s showed efficacy in a range of leukaemias (including Acute Myeloid Leukaemia), breast cancer, and ovarian cancer.[3]

Side effects

High doses of bisantrene (above 200 mg/m2/day) cause side effects typical of anthracycline chemotherapeutics. Common side effects include hair loss, bone marrow suppression, vomiting, rash, and inflammation of the mouth. For a chemotherapy drug, it is considered to have relatively low toxicity.[4]

Unlike other anthracycline chemotherapeutics, Bisantrene shows low levels of cardiotoxicity. In a Phase III metastatic breast cancer clinical, patients were exposed to cumulative doses in excess of 5440 mg/m2 without developing cardiac damage.[3] The same study observed significantly lower rates of hair loss and nausea compared to patients given doxorubicin.[5]

Mechanism of action

Bisantrene contains an appropriately sized planar electron-rich chromophore to be a DNA intercalating agent, and in vitro, it is a potent inhibitor of DNA and RNA synthesis.[3][4]

History

Bisantrene was developed by Lederle Laboratories during the 1970s, a subsidiary of American Cyanamid, as a less cardiotoxic alternative to anthracyclines. Across the 1980s and early 1990s, over 40 clinical trials were conducted using Bisantrene. The National Cancer Institute (NCI)] undertook a large scale trial using Bisantrene under the name "Orange Crush", including a range of preclinical trials which found bisantrene to be inactive when taken orally, though was found to be efficacy towards some cancer cells intravenous, intraperitoneal, or subcutaneous.

In the 1980s, forty-four patients with metastatic breast cancer who had undergone extensive combination chemotherapy with doxorubicin and had failed to respond to the combination, were treated with bisantrene. From 40 patients that were evaluated, 9 showed a partial response, and 18 showed the cancer was not progressive but stabilised.[6]

Bisantrene was approved for human medical use in France in 1990 to target Acute Myeloid Leukemia (AML) cancers.

It has undergone 46 Phase II trials with 1,800 patients to test its efficacy against fighting cancer cells.

The drug was delisted in the early 1990s due to a series of pharmaceutical mergers and acquisitions.

Society and culture

Names

Its chemical name is 9, 10-antrhracenedicarboxaldehydebis [(4, 5-dihydro-1H-imidazole-2-yl) hydrazine] dihydrochloride. Bisantrene was given the nickname “Orange Crush” in the 1980s due to its fluorescent orange color when in solution.[7]

Bisantrene is also referred to as CS1 in cancer research journals.[8]

References

  1. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. p. 126. ISBN 978-3-88763-075-1.
  2. ↑ "Bisantrene". PubChem. U.S. National Library of Medicine. Retrieved 2021-03-17.
  3. 1 2 3 4 Spiegel RJ, Blum RH, Levin M, Pinto CA, Wernz JC, Speyer JL, et al. (January 1982). "Phase I clinical trial of 9,10-anthracene dicarboxaldehyde (Bisantrene) administered in a five-day schedule". Cancer Research. 42 (1): 354–358. PMID 7053862.
  4. 1 2 Testa B (2013-10-22). Advances in Drug Research. Elsevier. pp. 69–72. ISBN 978-1-4832-8798-0.
  5. ↑ Cowan JD, Neidhart J, McClure S, Coltman CA, Gumbart C, Martino S, et al. (August 1991). "Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study". Journal of the National Cancer Institute. 83 (15): 1077–1084. doi:10.1093/jnci/83.15.1077. PMID 1875415.
  6. ↑ Yap HY, Yap BS, Blumenschein GR, Barnes BC, Schell FC, Bodey GP (March 1983). "Bisantrene, an active new drug in the treatment of metastatic breast cancer" (PDF). Cancer Research. 43 (3): 1402–1404. PMID 6825109.
  7. ↑ "Bisantrene Hydrochloride (Code C77218)". NCI Thesaurus. National Cancer Institute, U.S. Department of Health and Human Services. 28 June 2021. Archived from the original on 2021-07-12. Retrieved 12 July 2021.
  8. ↑ Su R, Dong L, Li Y, Gao M, Han L, Wunderlich M, et al. (July 2020). "Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion" (PDF). Cancer Cell. 38 (1): 79–96.e11. doi:10.1016/j.ccell.2020.04.017. PMC 7363590. PMID 32531268.
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