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Anthracyclines and anthracenedionesIn useNatural product

Doxorubicin

Also known as Adriamycin, 14-hydroxydaunomycin

An anthracycline given by injection that differs from daunorubicin by one hydroxyl group. Its 2020 US label lists adjuvant therapy for breast cancer with axillary node involvement and treatment of several leukaemias, lymphomas and solid tumours.

From discovery to approval

  1. 1969 · First described

    A 1969 paper by Arcamone and colleagues reported adriamycin from Streptomyces peucetius var. caesius, a strain obtained by mutagenic treatment of the daunomycin-producing S. peucetius. The abstract of the paper's 2000 reprint calls adriamycin the 14-hydroxy derivative of daunomycin.[2][3][4][5][6][7][8]

  2. 1974-08-07 · FDA regular · 5 years after first description

    Doxorubicin hydrochloride injection, NDA 050467, original approval, classed as a new molecular entity with priority review in the Drugs@FDA history. The original label and letter are not available there, so the indication at approval is not stated here; the 2020 label gives 1974 as the year of initial US approval. The type regular is an inference: no accelerated-approval wording was found.[9]

  3. 2003-05-08 · FDA regular · 34 years after first description

    Supplements 068 and 014 provide for use of doxorubicin hydrochloride for injection and injection in combination with cyclophosphamide as a component of adjuvant therapy in patients with evidence of axillary node tumour involvement following resection of primary breast cancer. The type regular is an inference: the letter has no accelerated-approval wording.[11]

How it works

The label says its cell-killing and organ toxicities are thought to relate to intercalation between nucleotide bases and binding to cell membrane lipids. Intercalation inhibits replication and the action of DNA and RNA polymerases; forming DNA-cleavable complexes with topoisomerase II appears to be an important mechanism.[1]

Where it came from and why

Cassinelli's review says the search for daunomycin's sister anthracyclines led to adriamycin. Arcamone's 1984 review states that, because the biosynthetic yield was low, chemical conversion of daunorubicin to adriamycin became the key step in developing the drug.

The Milan programme that produced daunomycin continued to look for related compounds, and Cassinelli describes adriamycin as the result of the search for daunomycin's sister anthracyclines [5]. A 1969 paper by Arcamone and colleagues reported it from Streptomyces peucetius var. caesius, a strain obtained by mutagenic treatment of the daunomycin-producing S. peucetius [3]. The abstract of the paper's 2000 reprint calls adriamycin the 14-hydroxy derivative of daunomycin [3], and Weiss notes that doxorubicin and daunorubicin differ by a single hydroxyl group [6].

Arcamone reports that the low yield of the biosynthetic process made chemical conversion of daunorubicin to adriamycin the key step in developing the drug [4]. In July 1969, according to Cassinelli, Di Marco sent Bonadonna the first vials to be tested in clinical trials [5]. Bonadonna and colleagues reported a clinical evaluation in the British Medical Journal that year, describing particular effectiveness in childhood malignancies and more stomatitis and alopecia than with daunorubicin [7], and a Tumori paper of 1969 by Monfardini and colleagues is titled as reporting clinical trials in leukaemia and solid tumours [8].

The FDA's Drugs@FDA history lists the original approval of doxorubicin hydrochloride on 7 August 1974 [9]. A 1979 analysis of 4018 patient records examined risk factors for doxorubicin-induced congestive heart failure [10].

Cancers

  • Breast cancer, adjuvant

    The 2020 US label lists use as a component of multiagent adjuvant chemotherapy in women with axillary lymph node involvement after resection of primary breast cancer; a 2003 FDA letter approved the combination with cyclophosphamide for this use.[1]

  • Other cancers on the label

    The 2020 US label also lists acute lymphoblastic and acute myeloblastic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and metastatic breast cancer, Wilms tumour, neuroblastoma, soft tissue sarcoma, bone sarcomas, and ovarian, transitional cell bladder, thyroid, gastric and bronchogenic carcinoma. The 2026 Pfizer label lists the same indications.[1]

  • Hodgkin lymphoma

    A 1975 randomised study compared a four-drug combination of adriamycin, bleomycin, vinblastine and imidazole carboxamide (ABVD) with MOPP in advanced Hodgkin disease.[12]

  • Non-Hodgkin lymphoma

    A 1976 series used CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) in advanced non-Hodgkin lymphoma and reported 71% complete remissions among 204 evaluable patients.[13]

  • Soft tissue sarcoma

    EORTC 62012 compared doxorubicin alone with intensified doxorubicin plus ifosfamide as first-line treatment of advanced or metastatic soft tissue sarcoma.[14]

Family and partners

Derived from: Daunorubicin

Drugs derived from it: Epirubicin, Valrubicin, Pirarubicin

Worth knowing

  • A retrospective analysis of 4018 patient records found doxorubicin-related congestive heart failure in 2.2% (88 cases); the probability rose with total dose, and a weekly schedule had a lower incidence than the usual 3-weekly schedule.[10]
  • The 2020 US label's boxed warning gives a cardiomyopathy incidence of 1% to 20% for cumulative doses of 300 to 500 mg/m2 when doxorubicin is given every 3 weeks.[1]
  • A 1992 review states that doxorubicin differs from daunorubicin only by a single hydroxyl group, which led researchers to look for analogues with less toxicity.[6]
  • In EORTC 62012, median overall survival was 12.8 months with doxorubicin alone and 14.3 months with intensified doxorubicin plus ifosfamide (hazard ratio 0.83, 95.5% CI 0.67 to 1.03; p=0.076); median progression-free survival was 4.6 and 7.4 months (hazard ratio 0.74, 95% CI 0.60 to 0.90).[14]
  • The 1969 British Medical Journal report describes adriamycin as having a structural formula very similar to daunorubicin and as particularly effective in childhood malignancies.[7]

On this site

References

  1. U.S. Food and Drug Administration. Doxorubicin hydrochloride injection and for injection, prescribing information (NDA 050467 supplement 078 and NDA 050629 supplement 030, 28 August 2020). Source
  2. Arcamone F, Cassinelli G, Fantini G, Grein A, Orezzi P, Pol C, et al. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol Bioeng. 1969;11(6):1101-10. PubMedDOI
  3. Arcamone F, Cassinelli G, Fantini G, Grein A, Orezzi P, Pol C, et al. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius (reprint of the 1969 paper). Biotechnol Bioeng. 2000;67(6):704-13. PubMedDOI
  4. Arcamone F. [Adriamycin and its analogs]. Tumori. 1984;70(2):113-9. PubMedDOI
  5. Cassinelli G. The roots of modern oncology: from discovery of new antitumor anthracyclines to their clinical use. Tumori. 2016;2016(3):226-35. PubMedDOI
  6. Weiss RB. The anthracyclines: will we ever find a better doxorubicin?. Semin Oncol. 1992;19(6):670-86. PubMed
  7. Bonadonna G, Monfardini S, De Lena M, Fossati-Bellani F. Clinical evaluation of adriamycin, a new antitumour antibiotic. Br Med J. 1969;3(5669):503-6. PubMedDOI
  8. Monfardini S, Bonadonna G, Di Pietro S, Guindani A, Fossati-Bellani F, De Lena M. [Clinical trials with adriamycin in leukemia and solid tumors]. Tumori. 1969;55(4):197-216. PubMedDOI
  9. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 050467 (doxorubicin hydrochloride). Page read 2026-10-29. Source
  10. Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91(5):710-7. PubMedDOI
  11. U.S. Food and Drug Administration. Approval letter, NDA 50-467/S-068/S-069 and NDA 50-629/S-014/S-016, doxorubicin hydrochloride, signed 8 May 2003. Source
  12. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252-9. PubMedDOI
  13. McKelvey EM, Gottlieb JA, Wilson HE, Haut A, Talley RW, Stephens R, et al. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer. 1976;38(4):1484-93. PubMedDOI
  14. Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415-23. PubMedDOI
  15. Hikma Pharmaceuticals USA Inc. Adriamycin (doxorubicin hydrochloride) injection, powder, lyophilized, for solution: prescribing information. DailyMed, set ID 090bc1b1-3dc2-408d-94e6-48d2a3d4426c, published 15 April 2024. Source
  16. Pfizer Laboratories Div Pfizer Inc. Doxorubicin hydrochloride injection, solution: prescribing information. DailyMed, set ID 1fd148fb-0fbc-4b6f-b790-23546fb46a71, published 7 May 2026. Source