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Phase II trial of dolastatin-10 in patients with advanced breast cancer

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Summary

Purpose: Phase II multicenter cooperative group study investigated the efficacy and toxicity of the novel anti-microtubule agent dolastatin-10 in patients with advanced breast cancer.

Patient and methods: Twenty-one patients with measurable metastatic breast cancer were treated with dolastatin-10 at a dose of 400 mcg/m2 by intravenous bolus once every 3 weeks. Patients must have received a total of 1 or 2 prior chemotherapy regimens and have an Eastern Cooperative Oncology Group performance status of 0–2. Patients received this treatment as either a first (n = 11) or second-line (n = 10) chemotherapy for metastatic disease. Eighteen patients (86%) had received a prior anthracycline. The National Cancer Institute provided the dolastatin-10.

Results: One out of 21 patients (5%; 95% CI: 0–24%) achieved a partial remission for a duration of 113 days. Four patients maintained stable disease for a median of 87 days. A total of 58 courses of dolastatin-10 were administered. Patients received a median of two cycles of dolastatin-10. Hematologic toxicity was moderate, with 8 patients developing grade 4 neutropenia, and 5 with grade 3 neutropenia; one grade 3 febrile neutropenia was observed. These episodes of grade 3 and 4 neutropenia were experienced on 36% of the treatment cycles. Non-hematologic toxicity was uncommon.

Conclusion: While the toxicity profile of dolastatin-10 was acceptable, it had minimal activity in this advanced breast cancer study. We are not pursuing further clinical trials of this agent in the setting of advanced breast cancer.

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References

  1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ: Cancer Statistics, 2005. CA Cancer J Clin 55: 10–30, 2003

    Article  Google Scholar 

  2. Perez EA: State of the Art Therapy for Metastatic Breast Cancer. Cancer Res Ther Control 9: 261–266, 1999

    Google Scholar 

  3. Pettit GR, Kamano Y, Herald CL, Tuinmann AA, Boettner FE, Kizu H, Schmidt JM, Baczynskyj L, Tomer KB, Bontems RJ: The isolation and structure of a remarkable marine animal antineoplastic constituent: Dolastatin-10. J Am Chem Soc 109: 6883–6885, 1997

    Article  Google Scholar 

  4. Kalemkerian GP, Ou X, Adil MR, et al. Activity of dolastatin-10 against small-cell cancer in vitro and in vivo: Induction of apoptosis and bcl-2 modification. Cancer Chemother Pharmacol 43: 507–515, 1999

    Article  CAS  PubMed  Google Scholar 

  5. Bai R, Pettit GR, Hamel E: Dolastatin 10, a powerful cytostatic peptide derived from a marine animal. Inhibition of tubulin polymerization mediated through the vinca alkaloid-binding domain. Biochem Pharmacol 39: 1941–1949, 1990

    Article  CAS  PubMed  Google Scholar 

  6. Bai RL, Pettit GR, Hamel E: Binding of dolastatin 10 to tubulin at a distinct site for peptide antimitotic agents near the exchangeable nucleotide and vinca alkaloid sites. J Biol Chem 265: 17141–17149, 1990

    CAS  PubMed  Google Scholar 

  7. Bai R, Roach MC, Jayaram SK, Barkoczy J, Pettit GR, Luduena RF, Hamel E: Differential effects of active isomers, segments, and analogs of dolastatin 10 on ligand interactions with tubulin. Correlation with cytotoxicity. Biochem Pharmacol 45: 1503–1515, 1993

    Article  CAS  PubMed  Google Scholar 

  8. Hamel E: Natural products which interact with tubulin in the vinca domain: maytansine, rhizoxin, phomopsin A, dolastatins 10 and 15 and halichondrin B. Pharmacol Ther 55: 31–51, 1992

    Article  CAS  PubMed  Google Scholar 

  9. Pettit GR, Singh SB, Hogan F: The absolute configuration and synthesis of natural dolastatin-10. J Am Chem Soc 111: 5463–5465, 1989

    Article  CAS  Google Scholar 

  10. Hu ZB, Gignac SM, Quentmeier H, Pettit GR, Drexler HG: Effects of dolastatins on human B-lymphocytic leukemia cell lines. Leuk Res 17: 333–339, 1993

    Article  CAS  PubMed  Google Scholar 

  11. Beckwith M, Urba WJ, Longo DL: Growth inhibition of human lymphoma cell lines by the marine products, dolastatins 10 and 15. J Natl Cancer Inst 85: 483–488, 1993

    CAS  PubMed  Google Scholar 

  12. Kingston RD, Fielding JW, Palmer MK: Peri-operative heparin: A possible adjuvant to surgery in colo-rectal cancer? Int J Colorectal Dis 8: 111–115, 1993

    Article  CAS  PubMed  Google Scholar 

  13. Pitot HC, McElroy EA Jr., Reid JM, Windebank AJ, Sloan JA, Erlichman C, Bagniewski PG, Walker DL, Rubin J, Goldberg RM, Adjei AA, Ames MM: Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors. Clin Cancer Res 5: 525–531, 1999

    CAS  PubMed  Google Scholar 

  14. Alroy I, Yarden Y: The ErbB signaling network in embryogenesis and oncogenesis: Signal diversification through combinatorial ligand-receptor interactions. FEBS Letters 410(1): 83–86, 1997

    Article  CAS  PubMed  Google Scholar 

  15. Maki A, Mohammad R, Raza S, Saleh M, Govindaraju KD, Pettit GR, al-Katib A: Effect of dolastatin 10 on human non-Hodgkin’s lymphoma cell lines. Anticancer Drugs 7: 344–350, 1996

    CAS  PubMed  Google Scholar 

  16. Kalemkerian GP, Ou X, Adil M, Rosati R, Khoulani M, Madan S, Pettit G: Activity of dolastatin-10 against small-cell lung cancer in vitro and in vivo: Induction of apoptosis and bcl-2 modification. Cancer Chemother Pharmacol 43: 507–515, 1999

    Article  CAS  PubMed  Google Scholar 

  17. Bai R, Friedman SJ, Pettit GR, Hamel E: Dolastatin 15, a potent antimitotic depsipeptide derived from Dolabella auricularia. Interaction with tubulin and effects of cellular microtubules. Biochem Pharmacol 43: 2637–2645, 1992

    Article  CAS  PubMed  Google Scholar 

  18. Quentmeier H, Brauer S, Pettit GR: Cytotoxic effects of dolastatin-10 and dolastatin-15 on human leukemia cell lines. Leuk Lymphoma 6: 245–250, 1992

    Google Scholar 

  19. May RD, Murphy MJ Jr., Erickson-Miller CL, Tomaszewski JE, Osborn BL, Page JG: Myelotoxicity evaluation of dolastatin-10 (NSC-376128) and swainsonine (NSC-614553) Using murine, canine and human in vitro CFU-GM assays (abstract #2398). Proc Am Assoc Cancer Res 35: 402, 1994

    Google Scholar 

  20. Krug LM, Miller VA, Kalemkerian GP, Kraut MJ, Ng KK, Heelan RT, Pizzo BA, Perez W, McClean N, Kris MG: Phase II study of dolastatin-10 in patients with advanced non-small-cell lung cancer. Ann Oncol 11: 227–228, 2000

    Article  CAS  PubMed  Google Scholar 

  21. Vaishampayan U, Glode M, Du W, Kraft A, Hudes G, Wright J, Hussain M: Phase II study of dolastatin-10 in patients with hormone-refractory metastatic prostate adenocarcinoma. Clin Cancer Res 6: 4205–4208, 2000

    CAS  PubMed  Google Scholar 

  22. Margolin K, Longmate J, Synold TW, Gandara DR, Weber J, Gonzalez R, Johansen MJ, Newman R, Baratta T, Doroshow JH: Dolastatin-10 in metastatic melanoma: A phase II and pharmokinetic trial of the California Cancer Consortium. Invest New Drugs 19: 335–340, 2001

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Mayo Clinic and Mayo Foundation, Rochester, MN, 55905, USA

    Edith A. Perez MD, David W. Hillman & Steven R. Alberts

  2. Oncology/Hematology Associates of Central Illinois, Peoria, IL, 61602, USA

    Paul A. Fishkin

  3. Duluth CCOP, Duluth, MN, 55805, USA

    James E. Krook

  4. Mayo Clinic, Jacksonville, FL, 32224, USA

    Edith A. Perez MD, Winston W. Tan & Phillip A. Kuriakose

  5. Cancer Center of Kansas, P.A., Wichita, KS, 67214, USA

    Shaker R. Dakhil

  6. Division of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida, 32224, USA

    Edith A. Perez MD

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  1. Edith A. Perez MD
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  2. David W. Hillman
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  3. Paul A. Fishkin
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  4. James E. Krook
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Correspondence to Edith A. Perez MD.

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Perez, E.A., Hillman, D.W., Fishkin, P.A. et al. Phase II trial of dolastatin-10 in patients with advanced breast cancer. Invest New Drugs 23, 257–261 (2005). https://doi.org/10.1007/s10637-005-6735-y

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  • DOI: https://doi.org/10.1007/s10637-005-6735-y

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