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A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer

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Abstract

Purpose

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a new and potent inhibitor of ribonucleotide reductase (RR), increases the cellular uptake, DNA incorporation, and cytotoxicity of gemcitabine in tumor cell lines. A phase I trial was initiated to determine the safety profile and maximum tolerated doses of 3-AP and gemcitabine when used in combination in patients with advanced cancer.

Study design

3-AP and gemcitabine were administered on days 1, 8, and 15 of each 28-day cycle. Initially, 3-AP was infused over 2 h at a fixed dose of 105 mg/m2. Gemcitabine was given over 30 min beginning no less than 1 and no more than 4 h after 3-AP. The first cohort received 3-AP alone in the first cycle. Subsequently, the gemcitabine dose was escalated beginning at 600 mg/m2 in cohorts of three to six patients. Following the gemcitabine 1000 mg/m2 dose level, the study was amended to determine if the 3-AP dose could be escalated above 105 mg/m2.

Results

3-AP at 105 mg/m2 administered over 2 h followed in 1–4 h by gemcitabine at 1000 mg/m2 produced a toxicity profile similar to that expected for gemcitabine alone at the same dose. When the dose of 3-AP was escalated to 140 and 185 mg/m2 administered over 2 h and subsequently over 4 h, acute hypotension, hypoxia, and EKG changes including non-specific ST-T wave changes and mild QT prolongation were observed, and one patient with underlying diffuse coronary artery disease had an asymptomatic myocardial infarction. 3-AP was shown to cause mild, reversible methemoglobinemia. Average end-of infusion serum concentrations for 3-AP at all doses were within the range capable of enhancing gemcitabine cytotoxicity in vitro. Gemcitabine plasma concentrations at end-of-infusion and elimination half-life were consistent with values reported in the literature. Among 22 evaluable patients, one complete response and two partial responses were observed, and an additional patient had prolonged stabilization of a large liver metastasis.

Conclusions

3-AP at 105 mg/m2 infused over 2–4 h followed by gemcitabine at 1000 mg/m2 on a days 1, 8, and 15 schedule every 28 days was generally well-tolerated and had a toxicity profile similar to that of gemcitabine alone. 3-AP produced mild to modest methemoglobinemia, which could cause acute symptoms in patients with limited pulmonary or cardiovascular reserve. The combination demonstrated antitumor activity and merits further exploration in phase II trials.

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References

  1. Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN, et al (1991) A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498

    CAS  PubMed  Google Scholar 

  2. Bentur Y, McGuigan M, Koren G (1991) Deferoxamine (desferrioxamine). New toxicities for an old drug. Drug Saf 6:37–46

    CAS  PubMed  Google Scholar 

  3. Bergman AM, Pinedo HM, Peters GJ (2002) Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine). Drug Resist Updat 5:19–33

    Article  CAS  PubMed  Google Scholar 

  4. Bhalla K, Swerdlow P, Grant S (1991) Effects of thymidine and hydroxyurea on the metabolism and cytotoxicity of 1-β-D-arabinofuranosylcytosine in highly resistant human leukemia cells. Blood 78:2937–2944

    CAS  PubMed  Google Scholar 

  5. Bokemeyer C, Gerl A, Schoffski P, Harstrick A, Niederle N, Beyer J, Casper J, Schmoll HJ, Kanz L (1999) Gemcitabine in patients with relapsed or cisplatin-refractory testicular cancer. J Clin Oncol 17:512–516

    CAS  PubMed  Google Scholar 

  6. Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413

    PubMed  Google Scholar 

  7. Cardenal F, Lopez-Cabrerizo MP, Anton A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, Garcia M, Lianes P, Montalar J, Vadell C, Gonzalez-Larriba JL, Nguyen B, Artal A, Rosell R (1999) Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 17:12–18

    CAS  PubMed  Google Scholar 

  8. Chen C-H, King I, Belcourt M (2002) Triapine, a ribonucleotide reductase inhibitor, enhances incorporation of gemcitabine into DNA and cytotoxicity to KB cells. Eur J Cancer 38:S26

    PubMed  Google Scholar 

  9. Coleman MD, Coleman NA (1996) Drug-induced methaemoglobinaemia. Treatment issues. Drug Saf 14:394–405

    Google Scholar 

  10. Colly LP, Richel DJ, Arentsen-Honders MW, Kester MG, ter Riet PM, Willemze R (1992) Increase in Ara-C sensitivity in Ara-C sensitive and -resistant leukemia by stimulation of the salvage and inhibition of the de novo pathway. Ann Hematol 65:26–32

    CAS  PubMed  Google Scholar 

  11. Cory JG, Cory AH, Rappa G, Lorico A, Liu MC, Lin TS, Sartorelli AC (1994) Inhibitors of ribonucleotide reductase. Comparative effects of amino- and hydroxy-substituted pyridine-2-carboxaldehyde thiosemicarbazones. Biochem Pharmacol 48:335–3344

    CAS  PubMed  Google Scholar 

  12. Crino L, Mosconi AM, Scagliotti G, Selvaggi G, Novello S, Rinaldi M, Della Giulia M, Gridelli C, Rossi A, Calandri C, De Marinis F, Noseda M, Tonato M (1999) Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol 17:2081–2085

    CAS  PubMed  Google Scholar 

  13. Einhorn LH, Stender MJ, Williams SD (1999) Phase II trial of gemcitabine in refractory germ cell tumors. J Clin Oncol 17:509–511

    CAS  PubMed  Google Scholar 

  14. Feun L, Modiano M, Lee K, Mao J, Marini A, Savaraj N, Plezia P, Almassian B, Colacino E, Fischer J, MacDonald S (2002) Phase I and pharmacokinetic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) using a single intravenous dose schedule. Cancer Chemother Pharmacol 50:223–229

    Article  CAS  PubMed  Google Scholar 

  15. Finch RA, Liu M, Grill SP, Rose WC, Loomis R, Vasquez KM, Cheng Y, Sartorelli AC (2000) Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): a potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem Pharmacol 59:983–991

    CAS  PubMed  Google Scholar 

  16. Galmarini CM, Clarke ML, Falette N, Puisieux A, Mackey JR, Dumontet C (2002) Expression of a non-functional p53 affects the sensitivity of cancer cells to gemcitabine. Int J Cancer 97:439–445

    Article  CAS  PubMed  Google Scholar 

  17. Gandhi V, Plunkett W (1990) Modulatory activity of 2′,2′-difluorodeoxycytidine on the phosphorylation and cytotoxicity of arabinosyl nucleosides. Cancer Res 50:3675–3680

    CAS  PubMed  Google Scholar 

  18. Gandhi V, Kemena A, Keating MJ, Plunkett W (1992) Fludarabine infusion potentiates arabinosylcytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia. Cancer Res 52:897–903

    CAS  PubMed  Google Scholar 

  19. Gandhi V, Robertson LE, Keating MJ, Plunkett W (1994) Combination of fludarabine and arabinosylcytosine for treatment of chronic lymphocytic leukemia: clinical efficacy and modulation of arabinosylcytosine pharmacology. Cancer Chemother Pharmacol 34:30–36

    Article  CAS  PubMed  Google Scholar 

  20. Goan YG, Zhou B, Hu E, Mi S, Yen Y (1999) Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line. Cancer Res 59:4204–4207

    CAS  PubMed  Google Scholar 

  21. Gupta N, Ahmed I, Steinberg H, Patel D, Nissel-Horowitz S, Mehrotra B (2002) Gemcitabine-induced pulmonary toxicity: case report and review of the literature. Am J Clin Oncol 25:96–100

    Article  PubMed  Google Scholar 

  22. Heinemann V (2003) Role of gemcitabine in the treatment of advanced and metastatic breast cancer. Oncology 64:191–206

    Article  CAS  PubMed  Google Scholar 

  23. Heinemann V, Hertel LW, Grindey GB, Plunkett W (1988) Comparison of the cellular pharmacokinetics and toxicity of 2′,2′-difluorodeoxycytidine and 1-beta-d-arabinofuranosylcytosine. Cancer Res 48:4024–4031

    CAS  PubMed  Google Scholar 

  24. Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, Plunkett W (1990) Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2′,2′-difluorodeoxycytidine. Mol Pharmacol 38:567–572

    CAS  PubMed  Google Scholar 

  25. Howell SB, Streifel JA, Pfeifle CE (1982) Modulation of the cellular pharmacology and clinical toxicity of 1-beta-d-arabinofuranosylcytosine. Med Pediatr Oncol 10:81–91

    PubMed  Google Scholar 

  26. Huang P, Plunkett W (1995) Fludarabine- and gemcitabine-induced apoptosis: incorporation of analogs into DNA is a critical event. Cancer Chemother Pharmacol 36:181–188

    Article  CAS  PubMed  Google Scholar 

  27. Iwasaki H, Huang P, Keating MJ, Plunkett W (1997) Differential incorporation of ara-C, gemcitabine, and fludarabine into replicating and repairing DNA in proliferating human leukemia cells. Blood 90:270–278

    CAS  PubMed  Google Scholar 

  28. Joerger M, Gunz A, Speich R, Pestalozzi BC (2002) Gemcitabine-related pulmonary toxicity. Swiss Med Wkly 132:17–20

    CAS  PubMed  Google Scholar 

  29. Keating MJ, O’Brien S, McLaughlin P, Dimopoulos M, Gandhi V, Plunkett W, Lerner S, Kantarjian H, Estey E (1996) Clinical experience with fludarabine in hemato-oncology. Hematol Cell Ther 38 [Suppl 2]:S83–S91

    CAS  PubMed  Google Scholar 

  30. Kubota M, Takimoto T, Tanizawa A, Akiyama Y, Mikawa H (1988) Differential modulation of 1-beta-d-arabinofuranosylcytosine metabolism by hydroxyurea in human leukemic cell lines. Biochem Pharmacol 37:1745–1749

    Article  CAS  PubMed  Google Scholar 

  31. von der Maase H (2003) Gemcitabine in transitional cell carcinoma of the urothelium. Expert Rev Anticancer Ther 3:11–19

    CAS  PubMed  Google Scholar 

  32. Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, Crawford CR, Cass CE (1998) Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 58:4349–4357

    CAS  PubMed  Google Scholar 

  33. Mackey JR, Yao SY, Smith KM, Karpinski E, Baldwin SA, Cass CE, Young JD (1999) Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. J Natl Cancer Inst 91:1876–1881

    Article  CAS  PubMed  Google Scholar 

  34. Markman M (2002) Second-line treatment of ovarian cancer with single-agent gemcitabine. Semin Oncol 29:9–10

    Article  CAS  Google Scholar 

  35. Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, Hagan K, Greenberg B, Colwell B, Zee B, Tu D, Ottaway J, Humphrey R, Seymour L (2003) Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:3296–3302

    Article  CAS  PubMed  Google Scholar 

  36. Muggia F, Gill I (1992) Drug-induced ischemic syndromes. In: Muggia FM, Green MD, Speyer JL (eds) Cancer treatment and the heart. The Johns Hopkins University, Baltimore, pp 359–371

  37. Pfeifle CE, Howell SB (1983) Phase I trial of cytarabine and hydroxyurea. Cancer Treat Rep 67:1127–1129

    CAS  PubMed  Google Scholar 

  38. Pourquier P, Gioffre C, Kohlhagen G, Urasaki Y, Goldwasser F, Hertel LW, Yu S, Pon RT, Gmeiner WH, Pommier Y (2002) Gemcitabine (2′,2′-difluoro-2′-deoxycytidine), an antimetabolite that poisons topoisomerase I. Clin Cancer Res 8:2499–2504

    CAS  PubMed  Google Scholar 

  39. Rauscher F III, Cadman E (1983) Biochemical and cytokinetic modulation of L1210 and HL-60 cells by hydroxyurea and effect on 1-beta-d-arabinofuranosylcytosine metabolism and cytotoxicity. Cancer Res 43:2688–2693

    CAS  PubMed  Google Scholar 

  40. Rosell R, Scagliotti G, Danenberg KD, Lord RV, Bepler G, Novello S, Cooc J, Crino L, Sanchez JJ, Taron M, Boni C, De Marinis F, Tonato M, Marangolo M, Gozzelino F, Di Costanzo F, Rinaldi M, Salonga D, Stephens C (2003) Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer. Oncogene 22:3548–3553

    Article  CAS  PubMed  Google Scholar 

  41. Ross DD, Cuddy DP (1994) Molecular effects of 2′,2′-difluorodeoxycytidine (gemcitabine) on DNA replication in intact HL-60 cells. Biochem Pharmacol 48:1619–1630

    Article  CAS  PubMed  Google Scholar 

  42. Roychowdhury DF, Cassidy CA, Peterson P, Arning M (2002) A report on serious pulmonary toxicity associated with gemcitabine-based therapy. Invest New Drugs 20:311–315

    Article  CAS  PubMed  Google Scholar 

  43. Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, Mattson K, Manegold C, Palmer MC, Gregor A, Nguyen B, Niyikiza C, Einhorn LH (2000) Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 18:122–130

    CAS  PubMed  Google Scholar 

  44. Scheithauer W (2002) Review of gemcitabine in biliary tract carcinoma. Semin Oncol 29:40–45

    Article  CAS  Google Scholar 

  45. Schilsky RL, Williams SF, Ultmann JE, Watson S (1987) Sequential hydroxyurea-cytarabine chemotherapy for refractory non-Hodgkin’s lymphoma. J Clin Oncol 5:419–425

    CAS  PubMed  Google Scholar 

  46. Seymour JF, Huang P, Plunkett W, Gandhi V (1996) Influence of fludarabine on pharmacokinetics and pharmacodynamics of cytarabine: implications for a continuous infusion schedule. Clin Cancer Res 2:653–658

    CAS  PubMed  Google Scholar 

  47. Streifel JA, Howell SB (1981) Synergistic interaction between 1-beta-d-arabinofuranosylcytosine, thymidine, and hydroxyurea against human B cells and leukemic blasts in vitro. Proc Natl Acad Sci U S A 78:5132–5136

    CAS  PubMed  Google Scholar 

  48. Tempero M, Plunkett W, Ruiz Van Haperen V, Hainsworth J, Hochster H, Lenzi R, Abbruzzese J (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21:3402–3408

    Article  PubMed  Google Scholar 

  49. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    CAS  PubMed  Google Scholar 

  50. Vander Els NJ, Miller V (1998) Successful treatment of gemcitabine toxicity with a brief course of oral corticosteroid therapy. Chest 114:1779–1781

    CAS  PubMed  Google Scholar 

  51. Venook AP, Egorin MJ, Rosner GL, Hollis D, Mani S, Hawkins M, Byrd J, Hohl R, Budman D, Meropol NJ, Ratain MJ (2000) Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565. J Clin Oncol 18:2780–2787

    CAS  PubMed  Google Scholar 

  52. Walsh CT, Craig RW, Agarwal RP (1980) Increased activation of 1-beta-d-arabinofuranosylcytosine by hydroxyurea in L1210 cells. Cancer Res 40:3286–3292

    CAS  PubMed  Google Scholar 

  53. Yen Y, Chow W, Leong L, Margolin K, Morgan R, Raschko J, Shibata S, Somlo G, Twardowski P, Frankel P, Longmate J, Synold T, Newman EM, Lenz HJ, Gandara D, Doroshow JH (2002) Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine: a California Cancer Consortium trial. Cancer Chemother Pharmacol 50:353–359

    Article  CAS  PubMed  Google Scholar 

  54. Zhou B, Mi S, Mo X, Shih J, Tsai J, Hu E, Hsu M, Kay K, Yen Y (2002) Time and sequence dependence of hydroxyurea in combination with gemcitabine in human KB cells. Anticancer Res 22:1369–1377

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Yun Yen, Kim Margolin & James Doroshow

  2. Moffitt Cancer Center, Tampa, FL, USA

    Mayer Fishman & Dan Sullivan

  3. Vion Pharmaceuticals, Inc., 4 Science Park, New Haven, CT 06511, USA

    Bonny Johnson, Caroline Clairmont & Mario Sznol

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  1. Yun Yen
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  2. Kim Margolin
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  3. James Doroshow
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  8. Mario Sznol
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Correspondence to Mario Sznol.

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Yen, Y., Margolin, K., Doroshow, J. et al. A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. Cancer Chemother Pharmacol 54, 331–342 (2004). https://doi.org/10.1007/s00280-004-0821-2

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