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Bending the Curve Trial by Trial
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Topoisomerase inhibitorsUsed in a few countriesRational design

Amsacrine

Also known as m-AMSA, AMSA, NSC 249992, Amsidine

A synthetic acridine given by intravenous infusion. Ireland's regulator lists it for adult acute leukaemia, and a 2012 paper calls it the first drug shown to act as a topoisomerase II poison.

From discovery to approval

  1. 1974 · Earliest report found

    The earliest report found is Cain and Atwell's 1974 paper on the experimental antitumour properties of three congeners of the acridylmethanesulphonanilide (AMSA) series (title only). A 1980 abstract describes m-AMSA as a synthetic aminoacridine DNA intercalator with experimental murine antitumour activity.[2][3][4][5][1]

  2. No approval is recorded on this site.

How it works

A 2012 study describes an intercalating acridine joined to a headgroup, designed as a DNA-binding agent but acting as a topoisomerase II poison. Much of its specificity lies in the headgroup; intercalation mainly raises its affinity for the enzyme-DNA cleavage complex.[1]

Where it came from and why

A 2012 paper says m-AMSA was designed as a DNA-binding agent. The 1980 papers describe it as a new drug in the National Cancer Institute drug development programme, entering clinical trials after extensive experimental study.

Cancers

  • Acute myeloid leukaemia

    In a randomised comparison of 96 patients with untreated acute nonlymphocytic leukaemia, an amsacrine regimen reached complete remission in 70% against 54% with a daunorubicin regimen (P=0.13).[6]

  • Other leukaemias, lymphoma and solid tumours

    A phase I study of 71 patients saw activity in acute myeloid leukaemia, blastic chronic myeloid leukaemia and chronic lymphocytic leukaemia, and in Hodgkin's disease, hepatoma and oesophageal carcinoma.[3]

  • Breast cancer

    A 1980 review of the National Cancer Institute programme reports that m-AMSA had demonstrated tumour activity in acute leukaemia and breast cancer.[4]

Worth knowing

  • A 2012 paper says m-AMSA is historically significant as the first drug demonstrated to function as a topoisomerase II poison.[1]
  • In the 1978 single-dose phase I study of 29 patients, the recommended starting dose for phase II trials was 120 mg per square metre every 4 weeks; antitumour activity was seen in one patient with ovarian carcinoma.[7]
  • In the 1989 comparison, more patients reached remission after one course of the amsacrine regimen than after one course of the daunorubicin regimen (48% against 28%, P=0.03).[6]
  • In the German AML2003 trial, multiagent consolidation with mitoxantrone and amsacrine did not improve 3-year overall survival over three cycles of high-dose cytarabine (64% against 69%, P=.18) and added gastrointestinal and hepatic toxicity.[8]
  • Ireland's Health Products Regulatory Authority publishes a summary of product characteristics for Amsidine (amsacrine) that lists induction and maintenance of remission in acute leukaemia of adults, with a first authorisation date of 5 March 1984.[9]

References

  1. Ketron AC, Denny WA, Graves DE, Osheroff N. Amsacrine as a topoisomerase II poison: importance of drug-DNA interactions. Biochemistry. 2012;51(8):1730-9. PubMedDOI
  2. Cain BF, Atwell GJ. The experimental antitumour properties of three congeners of the acridylmethanesulphonanilide (AMSA) series. Eur J Cancer (1965). 1974;10(8):539-49. PubMedDOI
  3. Goldsmith MA, Bhardwaj S, Ohnuma T, Greenspan EM, Holland JF. Phase I study of m-AMSA in patients with solid tumors and leukemias. Cancer Clin Trials. 1980;3(3):197-202. PubMed
  4. Weiss RB, Charles LM Jr, Macdonald JS. m-AMSA: an exciting new drug in the National Cancer Institute Drug Development Program. Cancer Clin Trials. 1980;3(3):203-9. PubMed
  5. Rozencweig M, Von Hoff DD, Legha SS, Cysyk RL, Muggia FM. m-AMSA: a new anticancer agent. Recent Results Cancer Res. 1980;74:250-7. PubMedDOI
  6. Berman E, Arlin ZA, Gaynor J, Miller W, Gee T, Kempin SJ, et al. Comparative trial of cytarabine and thioguanine in combination with amsacrine or daunorubicin in patients with untreated acute nonlymphocytic leukemia: results of the L-16M protocol. Leukemia. 1989;3(2):115-21. PubMed
  7. Von Hoff DD, Howser K, Gormley P, Bender RA, Glaubiger D, Levine AS, et al. Phase I study of methanesulfonamide, N-[4-(9-acridinylamino)-3-methoxyphenyl]-(m-AMSA) using a single-dose schedule. Cancer Treat Rep. 1978;62(10):1421-6. PubMed
  8. Schaich M, Parmentier S, Kramer M, Illmer T, Stölzel F, Röllig C, et al. High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial. J Clin Oncol. 2013;31(17):2094-102. PubMedDOI
  9. Health Products Regulatory Authority (Ireland). Summary of Product Characteristics, Amsidine 75 mg/1.5 ml concentrate and solvent for concentrate for solution for infusion (authorisation PA1591/002/001, Eurocept International BV); document dated 16 February 2023, text revised November 2019. Source