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Topoisomerase inhibitorsIn useDerivative of an earlier drug

Topotecan

Also known as Hycamtin, SK&F 104864

A semisynthetic, water-soluble derivative of camptothecin given by injection. The 2019 US label lists metastatic ovarian cancer, platinum-sensitive small cell lung cancer, and, with cisplatin, stage IV-B, recurrent or persistent cervical cancer.

From discovery to approval

  1. 1991 · Earliest report found

    Kingsbury and colleagues reported water-soluble aminoalkyl camptothecin analogues in 1991, most made from natural camptothecin, and chose SK&F 104864 for development; their abstract does not use the name topotecan. Papers of 1991 and 1992 title SK&F 104864 as topotecan.[2][3][4][5][6]

  2. 1996-05-28 · FDA regular

    Treatment of patients with metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy. The type regular is an inference: the letter has no accelerated-approval wording.[7]

  3. 1998-11-30 · FDA regular

    Treatment of small cell lung cancer sensitive disease after failure of first-line chemotherapy (supplement S-004). The letter shows no date; the date used is the action date Drugs@FDA lists (the letter states a user fee goal date of 5 December 1998). The type regular is an inference: the letter has no accelerated-approval wording.[8]

  4. 2006-06-14 · FDA regular

    In combination with cisplatin, treatment of stage IV-B, recurrent or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy (supplement S-014). The letter body shows no date; its electronic signature page is dated 6/14/2006, the same as the Drugs@FDA action date. The type regular is an inference: the letter has no accelerated-approval wording.[9]

How it works

The label says topotecan binds the topoisomerase I-DNA complex and prevents re-ligation of single-strand breaks; cytotoxicity is thought to come from double-strand DNA damage during DNA synthesis, which mammalian cells cannot efficiently repair.[1]

Where it came from and why

The aim was water-soluble camptothecin analogues. A 2006 review says the water-soluble sodium salt of camptothecin, introduced in early trials in the 1960s, was highly toxic in animals and that topotecan, unlike it, did not cause haemorrhagic cystitis; the 1992 phase I report found no haemorrhagic cystitis either.

Cancers

  • Ovarian cancer

    In a randomised trial of 226 patients with recurrent epithelial ovarian cancer after one platinum-based regimen, topotecan and paclitaxel had response rates of 20.5% and 13.2% (P=.138), with a longer time to progression for topotecan (23 against 14 weeks, P=.002).[10]

  • Small cell lung cancer

    In a randomised trial of 211 patients with relapsed small cell lung cancer, topotecan and cyclophosphamide, doxorubicin and vincristine had response rates of 24.3% and 18.3% (P=.285) and similar median survival (25.0 and 24.7 weeks).[11]

  • Cervical cancer

    In a Gynecologic Oncology Group trial of 294 patients, adding topotecan to cisplatin gave a median overall survival of 9.4 months against 6.5 months with cisplatin alone (P=.017).[12]

Family and partners

Derived from: Camptothecin

Worth knowing

  • The 1992 phase I report called topotecan the first topoisomerase I-targeting agent to enter clinical development in the United States since studies of sodium camptothecin more than two decades earlier; unlike sodium camptothecin, it did not cause haemorrhagic cystitis.[5]
  • A 2006 review says that, unlike irinotecan, topotecan is primarily excreted by the kidneys.[6]
  • In the European phase II study, 111 patients with ovarian cancer after one cisplatin-based regimen entered and 92 were assessable; the response rate was 16.3% overall (5.9% in cisplatin-refractory, 17.8% in cisplatin-resistant and 26.7% in cisplatin-sensitive patients).[13]

On this site

References

  1. U.S. Food and Drug Administration. Hycamtin (topotecan) for injection, prescribing information, NDA 020671 supplement 024 (action date 8 October 2019; Initial U.S. Approval 1996). Source
  2. Kingsbury WD, Boehm JC, Jakas DR, Holden KG, Hecht SM, Gallagher G, et al. Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I and antitumor activity. J Med Chem. 1991;34(1):98-107. PubMedDOI
  3. Mattern MR, Hofmann GA, McCabe FL, Johnson RK. Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864). Cancer Res. 1991;51(21):5813-6. PubMed
  4. Wall JG, Burris HA 3rd, Von Hoff DD, Rodriguez G, Kneuper-Hall R, Shaffer D, et al. A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F 104864) given as an intravenous bolus every 21 days. Anticancer Drugs. 1992;3(4):337-45. PubMedDOI
  5. Rowinsky EK, Grochow LB, Hendricks CB, Ettinger DS, Forastiere AA, Hurowitz LA, et al. Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol. 1992;10(4):647-56. PubMedDOI
  6. Hartmann JT, Lipp HP. Camptothecin and podophyllotoxin derivatives: inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profile. Drug Saf. 2006;29(3):209-30. PubMedDOI
  7. U.S. Food and Drug Administration. Approval letter, NDA 20-671, Hycamtin (topotecan hydrochloride) 4 mg for Injection, SmithKline Beecham Pharmaceuticals, dated 28 May 1996 (page 6 of FDA's historical file for the application). Source
  8. U.S. Food and Drug Administration. Supplement approval letter, NDA 20-671/S-004, Hycamtin (topotecan hydrochloride) for Injection, SmithKline Beecham Pharmaceuticals (the letter shows no date and states a user fee goal date of 5 December 1998; Drugs@FDA lists the action date as 30 November 1998). Source
  9. U.S. Food and Drug Administration. Supplement approval letter, NDA 20-671/S-014, Hycamtin (topotecan hydrochloride) for Injection, SmithKline Beecham d/b/a GlaxoSmithKline (the letter body shows no date; its electronic signature page is dated 6/14/2006, as is the Drugs@FDA action date). Source
  10. ten Bokkel Huinink W, Gore M, Carmichael J, Gordon A, Malfetano J, Hudson I, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol. 1997;15(6):2183-93. PubMedDOI
  11. von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17(2):658-67. PubMedDOI
  12. Long HJ 3rd, Bundy BN, Grendys EC Jr, Benda JA, McMeekin DS, Sorosky J, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol. 2005;23(21):4626-33. PubMedDOI
  13. Creemers GJ, Bolis G, Gore M, Scarfone G, Lacave AJ, Guastalla JP, et al. Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol. 1996;14(12):3056-61. PubMedDOI
  14. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 020671 (Hycamtin, topotecan hydrochloride). Page read 2026-10-29. Source