nach oben

Erschienen in:

01.08.2011 | Original Article

Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer

verfasst von: Allyson J. Ocean, Paul Christos, Joseph A. Sparano, Dan Matulich, Andreas Kaubish, Abby Siegel, Max Sung, Maureen M. Ward, Nancy Hamel, Igor Espinoza-Delgado, Yun Yen, Maureen E. Lane

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2011

Einloggen, um Zugang zu erhalten

Abstract

Background

3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP) is a novel small molecule ribonucleotide reductase (RR) inhibitor which is more potent than hydroxyurea, the prototype of RR inhibitors. 3-AP enhances the cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. We evaluated the combination of 3-AP plus gemcitabine in advanced biliary tract adenocarcinoma.

Methods

Thirty-three patients with advanced adenocarcinoma of the gall bladder or biliary tract received gemcitabine (1,000 mg/m² on days 1, 8, and 15 every 28 days) 1 h after completing a 4-h infusion of 3-AP given at a dose of 105 mg/m² in patients with normal liver function (stratum A) or 80 mg/m² if abnormal liver function (stratum B). The trial was designed to determine whether the response rate was at least 30% in stratum A and 20% in stratum B.

Results

Objective response occurred in 3 of 23 patients (13%, 95% confidence intervals [CI] 3, 34%) with normal liver function, and in 0 of 10 patients with abnormal liver function. The most common grade 3–4 adverse events in all patients included neutropenia (42%), infection (33%), thrombocytopenia (27%), anemia (18%), and fatigue (15%). Fine needle aspiration of tumor samples obtained before and 24 h after 3-AP therapy showed increased R2 mRNA expression by in situ RT–PCR, suggesting RR inhibition.

Conclusions

Despite evidence for RR inhibition in vivo, the 3-AP plus gemcitabine combination is not likely to be associated with a response rate exceeding 30% in patients with adenocarcinoma of the biliary tract.

Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249PubMedCrossRef

Choi BI, Han JK, Hong ST et al (2004) Clonorchiasis and cholangiocarcinoma: etiologic relationship and imaging diagnosis. Clin Microbiol Rev 17:540–52 ( table of contents)

Chang KY, Chang JY, Yen Y (2009) Increasing incidence of intrahepatic cholangiocarcinoma and its relationship to chronic viral hepatitis. J Natl Compr Canc Netw 7:423–427PubMed

de Groen PC, Gores GJ, LaRusso NF et al (1999) Biliary tract cancers. N Engl J Med 341:1368–1378PubMedCrossRef

Park JS, Oh SY, Kim SH et al (2005) Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study. Jpn J Clin Oncol 35:68–73PubMedCrossRef

Eng C, Ramanathan RK, Wong MK et al (2004) A phase II trial of fixed dose rate gemcitabine in patients with advanced biliary tree carcinoma. Am J Clin Oncol 27:565–569PubMedCrossRef

Tsavaris N, Kosmas C, Gouveris P et al (2004) Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest New Drugs 22:193–198PubMedCrossRef

Kuhn R, Hribaschek A, Eichelmann K et al (2002) Outpatient therapy with gemcitabine and docetaxel for gallbladder, biliary, and cholangio-carcinomas. Invest New Drugs 20:351–356PubMedCrossRef

Valle JW, Wasan H, Johnson P et al (2009) Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study—The UK ABC-01 Study. Br J Cancer 101:621–627PubMedCrossRef

10.

Valle J, Wasan H, Palmer DH et al (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273–81

11.

Cory JG, Sato A (1983) Regulation of ribonucleotide reductase activity in mammalian cells. Mol Cell Biochem 53–54:257–266PubMed

12.

Fan H, Villegas C, Huang A et al (1998) The mammalian ribonucleotide reductase R2 component cooperates with a variety of oncogenes in mechanisms of cellular transformation. Cancer Res 58:1650–1653PubMed

13.

Cory JG, Cory AH, Rappa G et al (1994) Inhibitors of ribonucleotide reductase. Comparative effects of amino- and hydroxy-substituted pyridine-2-carboxaldehyde thiosemicarbazones. Biochem Pharmacol 48:335−344PubMedCrossRef

14.

Liu MC, Lin TS, Cory JG et al (1996) Synthesis and biological activity of 3- and 5-amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone. J Med Chem 39:2586–2593PubMedCrossRef

15.

Elford HL, Freese M, Passamani E et al (1970) Ribonucleotide reductase and cell proliferation. I. Variations of ribonucleotide reductase activity with tumor growth rate in a series of rat hepatomas. J Biol Chem 245:5228–5233PubMed

16.

Zhou B, Mi S, Mo X et al (2002) Time and sequence dependence of hydroxyurea in combination with gemcitabine in human KB cells. Anticancer Res 22:1369−77PubMed

17.

Finch RA, Liu M, Grill SP et al (2000) Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): a potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem Pharmacol 59:983–991PubMedCrossRef

18.

Finch RA, Liu MC, Cory AH et al (1999) Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): an inhibitor of ribonucleotide reductase with antineoplastic activity. Adv Enzyme Regul 39:3–12PubMedCrossRef

19.

Sigmond J, Kamphuis JA, Laan AC et al (2007) The synergistic interaction of gemcitabine and cytosine arabinoside with the ribonucleotide reductase inhibitor triapine is schedule dependent. Biochem Pharmacol 73:1548–1557PubMedCrossRef

20.

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

21.

Foltz LM, Dalal BI, Wadsworth LD et al (2006) Recognition and management of methemoglobinemia and hemolysis in a G6PD-deficient patient on experimental anticancer drug Triapine. Am J Hematol 81:210–211PubMedCrossRef

22.

Therasse P, Arbuck SG, Eisenhauer EA et al (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 92:205–216PubMedCrossRef

23.

Wadler S, Zhang H, Cammer M et al (1999) Quantification of ribonucleotide reductase expression in wild-type and hydroxyurea-resistant cell lines employing in situ reverse transcriptase polymerase chain reaction and a computerized image analysis system. Anal Biochem 267:24–29PubMedCrossRef

24.

Knox JJ, Hotte SJ, Kollmannsberger C et al (2007) Phase II study of Triapine in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC IND.161). Invest New Drugs 25:471–477PubMedCrossRef

25.

Attia S, Kolesar J, Mahoney MR et al (2008) A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas. Invest New Drugs 26:369–379PubMedCrossRef

26.

Mackenzie MJ, Saltman D, Hirte H et al (2007) A Phase II study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) and gemcitabine in advanced pancreatic carcinoma. A trial of the Princess Margaret hospital Phase II consortium. Invest New Drugs 25:553–558PubMedCrossRef

27.

Ma B, Goh BC, Tan EH et al (2008) A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells. Invest New Drugs 26:169–173PubMedCrossRef

28.

Yee KW, Cortes J, Ferrajoli A et al (2006) Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome. Leuk Res 30:813–822PubMedCrossRef

29.

Wadler S, Horowitz R, Zhang HY et al (1998) Effects of perturbations of pools of deoxyribonucleoside triphosphates on expression of ribonucleotide reductase, a G1/S transition state enzyme, in p53-mutated cells. Biochem Pharmacol 55:1353–1360PubMedCrossRef

30.

Zhang YW, Jones TL, Martin SE et al (2009) Implication of checkpoint kinase-dependent up-regulation of ribonucleotide reductase R2 in DNA damage response. J Biol Chem 284:18085–18095PubMedCrossRef

31.

Yamaguchi T, Matsuda K, Sagiya Y et al (2001) p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint. Cancer Res 61:8256–8262PubMed

32.

Devlin HL, Mack PC, Burich RA et al (2008) Impairment of the DNA repair and growth arrest pathways by p53R2 silencing enhances DNA damage-induced apoptosis in a p53-dependent manner in prostate cancer cells. Mol Cancer Res 6:808–818PubMedCrossRef

33.

Mortazavi A, Dearn, D, Ling, Y, Harper EJ, Phelps MA, Espinoza-Delgado I, Monk JP, Otterson GA, Grever MR, Belkaii-Saab T (2010) A phase I study of prolonged infusion of triapine in combination with fixed-dose rate of gemcitabine in patients with advanced solid tumors. Proceedings of the American Society of Clinical Oncology Abstract 53259

34.

Kunos CA, Waggoner S, von Gruenigen V, et al (2010) Phase I trial of pelvic radiation, weekly cisplatin, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) for locally advanced cervical cancer. Clin Cancer Res 16:1298–1306

Titel: Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer
verfasst von: Allyson J. Ocean
Paul Christos
Joseph A. Sparano
Dan Matulich
Andreas Kaubish
Abby Siegel
Max Sung
Maureen M. Ward
Nancy Hamel
Igor Espinoza-Delgado
Yun Yen
Maureen E. Lane
Publikationsdatum: 01.08.2011
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2011
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1481-z

Neu im Fachgebiet Onkologie

Umsetzung der POMGAT-Leitlinie läuft

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Springer Medizin

Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer