Investigational New Drugs

, Volume 25, Issue 2, pp 131–138 | Cite as

Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors

  • Luis H. Camacho
  • Jon Olson
  • William P. Tong
  • Charles W. Young
  • David R. Spriggs
  • Mark G. Malkin
Phase I Studies

Abstract

Background: Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown.

Methods: We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60–360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each.

Results: Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA ≥1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively.

Conclusions: Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.

Keywords

Phenylbutyrate Cellular differentiation Phase I Histone acetylation 

Notes

Acknowledgments

The authors would like to acknowledge the support and guidance of Jamie Zwiebel, MD at the Clinical Investigational Branch; Cancer Therapy Evaluation Program at the National Cancer Institute, Bethesda, MD.

References

  1. 1.
    Kritchevsky D, Moyer AW, Tesar WC, McCandless RF, Logan JB, Brown RA, et al (1956) The effect of sodium 2-phenylbutyrate in experimental atherosclerosis. Angiology 7(2):156–158PubMedGoogle Scholar
  2. 2.
    Brusilow SW (1991) Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion. Pediatr Res 29(2):147–150PubMedGoogle Scholar
  3. 3.
    Brusilow SW, Danney M, Waber LJ, Batshaw M, Burton B, Levitsky L, et al (1984) Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis. N Engl J Med 310(25):1630–1634PubMedCrossRefGoogle Scholar
  4. 4.
    Samid D, Shack S, Sherman LT (1992) Phenylacetate: a novel nontoxic inducer of tumor cell differentiation. Cancer Res 52(7):1988–1992PubMedGoogle Scholar
  5. 5.
    DiGiuseppe JA, Weng LJ, Yu KH, Fu S, Kastan MB, Samid D, et al (1999) Phenylbutyrate-induced G1 arrest and apoptosis in myeloid leukemia cells: structure-function analysis. Leukemia 13(8):1243–1253PubMedCrossRefGoogle Scholar
  6. 6.
    Carducci MA, Nelson JB, Chan-Tack KM, Ayyagari SR, Sweatt WH, Campbell PA, et al (1996) Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. Clin Cancer Res 2(2):379–387PubMedGoogle Scholar
  7. 7.
    Samid D, Hudgins WR, Shack S, Liu L, Prasanna P, Myers CE (1997) Phenylacetate and phenylbutyrate as novel, nontoxic differentiation inducers. Adv Exp Med Biol 400A:501–505PubMedGoogle Scholar
  8. 8.
    Warrell RP, Jr, He LZ, Richon V, Calleja E, Pandolfi PP (1998) Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 90(21):1621–1625PubMedCrossRefGoogle Scholar
  9. 9.
    Han S, Wada RK, Sidell N (2001) Differentiation of human neuroblastoma by phenylacetate is mediated by peroxisome proliferator-activated receptor gamma. Cancer Res 61(10):3998–4002PubMedGoogle Scholar
  10. 10.
    Lea MA, Sura M, Desbordes C (2004) Inhibition of cell proliferation by potential peroxisome proliferator-activated receptor (PPAR) gamma agonists and antagonists. Anticancer Res 24(5A):2765–2771PubMedGoogle Scholar
  11. 11.
    Darmaun D, Welch S, Rini A, Sager BK, Altomare A, Haymond MW (1998) Phenylbutyrate-induced glutamine depletion in humans: effect on leucine metabolism. Am J Physiol 274(5 Pt 1):E801–E807PubMedGoogle Scholar
  12. 12.
    Nichols KE, Weinberg JB (1989) Essential amino acid deprivation induces monocytic differentiation of the human HL-60 myeloid leukemia cell line. Blood 73(5):1298–1306PubMedGoogle Scholar
  13. 13.
    Zhang X, Wei L, Yang Y, Yu Q (2004) Sodium 4-phenylbutyrate induces apoptosis of human lung carcinoma cells through activating JNK pathway. J Cell Biochem 93(4):819–829PubMedCrossRefGoogle Scholar
  14. 14.
    Thibault A, Cooper MR, Figg WD, Venzon DJ, Sartor AO, Tompkins AC, et al (1994) A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer. Cancer Res 54(7):1690–1694PubMedGoogle Scholar
  15. 15.
    Rudek MA, Zhao M, He P, Hartke C, Gilbert J, Gore SD, et al (2005) Pharmacokinetics of 5-azacitidine administered with phenylbutyrate in patients with refractory solid tumors or hematologic malignancies. J Clin Oncol 23(17):3906–3911PubMedCrossRefGoogle Scholar
  16. 16.
    Phuphanich S, Baker SD, Grossman SA, Carson KA, Gilbert MR, Fisher JD, et al (2005) Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study. Neuro-oncol 7(2):177–182PubMedCrossRefGoogle Scholar
  17. 17.
    Carducci MA, Gilbert J, Bowling MK, Noe D, Eisenberger MA, Sinibaldi V, et al (2001) A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule. Clin Cancer Res 7(10):3047–3055PubMedGoogle Scholar
  18. 18.
    Gore SD, Weng LJ, Figg WD, Zhai S, Donehower RC, Dover G, et al (2002) Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res 8(4):963–970PubMedGoogle Scholar
  19. 19.
    Gilbert J, Baker SD, Bowling MK, Grochow L, Figg WD, Zabelina Y, et al (2001) A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res 7(8):2292–2300PubMedGoogle Scholar
  20. 20.
    Boudoulas S, Lush RM, McCall NA, Samid D, Reed E, Figg WD (1996) Plasma protein binding of phenylacetate and phenylbutyrate, two novel antineoplastic agents. Ther Drug Monit 18(6):714–720PubMedCrossRefGoogle Scholar
  21. 21.
    O'Quigley J, Chevret S (1991) Methods for dose finding studies in cancer clinical trials: a review and results of a Monte Carlo study. Stat Med 10(11):1647–1664PubMedGoogle Scholar
  22. 22.
    Piscitelli SC, Thibault A, Figg WD, Tompkins A, Headlee D, Lieberman R, et al (1995) Disposition of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine. J Clin Pharmacol 35(4):368–373PubMedGoogle Scholar
  23. 23.
    Thibault A, Figg WD, McCall N, Myers CE, Cooper MR (1994) A simultaneous assay of the differentiating agents phenylacetate and phenylbutyrate, and one of their metabolites, phenylglutamine, by reversed-phase, high performance liquid chromatography. J Liq Chromatogr 17:2895–2900Google Scholar
  24. 24.
    Thibault A, Samid D, Cooper MR, Figg WD, Tompkins AC, Patronas N, et al (1995) Phase I study of phenylacetate administered twice daily to patients with cancer. Cancer 75(12):2932–2938PubMedCrossRefGoogle Scholar
  25. 25.
    Coffey DC, Kutko MC, Glick RD, Swendeman SL, Butler L, Rifkind R, et al (2000) Histone deacetylase inhibitors and retinoic acids inhibit growth of human neuroblastoma in vitro. Med Pediatr Oncol 35(6):577–581PubMedCrossRefGoogle Scholar
  26. 26.
    Karasawa Y, Murakami A, Okisaka S (2000) Apoptosis after butyrate-induced differentiation in retinoblastoma cell line Y-79. Jpn J Ophthalmol 44(6):601–609PubMedCrossRefGoogle Scholar
  27. 27.
    Pelidis MA, Carducci MA, Simons JW (1998) Cytotoxic effects of sodium phenylbutyrate on human neuroblastoma cell lines. Int J Oncol 12(4):889–893PubMedGoogle Scholar
  28. 28.
    Berg S, Serabe B, Aleksic A, Bomgaars L, McGuffey L, Dauser R, et al (2001) Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate. Cancer Chemother Pharmacol 47(5):385–390PubMedCrossRefGoogle Scholar
  29. 29.
    Rocchi P, Ferreri AM, Magrini E, Perocco P (1998) Effect of butyrate analogues on proliferation and differentiation in human neuroblastoma cell lines. Anticancer Res 18(2A):1099–1103PubMedGoogle Scholar
  30. 30.
    Stockhammer G, Manley GT, Johnson R, Rosenblum MK, Samid D, Lieberman FS (1995) Inhibition of proliferation and induction of differentiation in medulloblastoma- and astrocytoma-derived cell lines with phenylacetate. J Neurosurg 83(4):672–681PubMedCrossRefGoogle Scholar
  31. 31.
    Sidell N, Wada R, Han G, Chang B, Shack S, Moore T, et al (1995) Phenylacetate synergizes with retinoic acid in inducing the differentiation of human neuroblastoma cells. Int J Cancer 60(4):507–514PubMedGoogle Scholar
  32. 32.
    Ram Z, Samid D, Walbridge S, Oshiro EM, Viola JJ, Tao-Cheng JH, et al (1994) Growth inhibition, tumor maturation, and extended survival in experimental brain tumors in rats treated with phenylacetate. Cancer Res 54(11):2923–2927PubMedGoogle Scholar
  33. 33.
    Samid D, Yeh TJ, Shack S (1991) Interferon in combination with antitumourigenic phenyl derivatives: potentiation of IFN alpha activity in-vitro. Br J Haematol 79(Suppl 1):81–83PubMedGoogle Scholar
  34. 34.
    Gorospe M, Shack S, Guyton KZ, Samid D, Holbrook NJ (1996) Up-regulation and functional role of p21Waf1/Cip1 during growth arrest of human breast carcinoma MCF-7 cells by phenylacetate. Cell Growth Differ 7(12):1609–1615PubMedGoogle Scholar
  35. 35.
    Bar-Ner M, Thibault A, Tsokos M, Magrath IT, Samid D (1999) Phenylbutyrate induces cell differentiation and modulates Epstein-Barr virus gene expression in Burkitt's lymphoma cells. Clin Cancer Res 5(6):1509–1516PubMedGoogle Scholar
  36. 36.
    Shack S, Miller A, Liu L, Prasanna P, Thibault A, Samid D (1996) Vulnerability of multidrug-resistant tumor cells to the aromatic fatty acids phenylacetate and phenylbutyrate. Clin Cancer Res 2(5):865–872PubMedGoogle Scholar
  37. 37.
    Samid D, Yeh A, Prasanna P (1992) Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. Blood 80(6):1576–1581PubMedGoogle Scholar
  38. 38.
    Fibach E, Prasanna P, Rodgers GP, Samid D (1993) Enhanced fetal hemoglobin production by phenylacetate and 4-phenylbutyrate in erythroid precursors derived from normal donors and patients with sickle cell anemia and beta-thalassemia. Blood 82(7):2203–2209PubMedGoogle Scholar
  39. 39.
    Young CW, Fanucchi MP, Declan Walsh T, Baltzer L, Yaldaei S, Stevens YW, et al (1988) Phase I trial and clinical pharmacological evaluation of hexamethylene bisacetamide administration by ten-day continuous intravenous infusion at twenty-eight-day intervals. Cancer Res 48(24 Pt 1):7304–7309PubMedGoogle Scholar
  40. 40.
    Andreeff M, Stone R, Michaeli J, Young CW, Tong WP, Sogoloff H, et al (1992) Hexamethylene bisacetamide in myelodysplastic syndrome and acute myelogenous leukemia: a phase II clinical trial with a differentiation-inducing agent. Blood 80(10):2604–2609PubMedGoogle Scholar
  41. 41.
    Maslak P, Chanel S, Camacho LH, Soignet S, Pandolfi PP, Guernah I, et al (2006) Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 20(2):212–217PubMedCrossRefGoogle Scholar
  42. 42.
    Camacho LH, Novick S, Tolentino T, Tong WP, Richon V, Warrell RP, Jr (2006) Clinical modulation of gene transcription Via inhibition of histone deacetylase using all-trans retinoic acid plus sodium phenylbutyrate. In: Proceedings of the Am Soc Clin Oncol, 2000, New Orleans, 2000, p 461aGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Luis H. Camacho
    • 1
    • 4
  • Jon Olson
    • 2
  • William P. Tong
    • 3
  • Charles W. Young
    • 1
  • David R. Spriggs
    • 1
  • Mark G. Malkin
    • 2
    • 5
  1. 1.Department of MedicineMemorial Sloan-Kettering Cancer Center, Joan and Sanford I. Weill Medical College of Cornell Medical CenterNew YorkUSA
  2. 2.Department of NeurologyMemorial Sloan-Kettering Cancer Center, Joan and Sanford I. Weill Medical College of Cornell Medical CenterNew YorkUSA
  3. 3.Department of Molecular BiologyMemorial Sloan-Kettering Cancer Center, Joan and Sanford I. Weill Medical College of Cornell Medical CenterNew YorkUSA
  4. 4.Phase I Program, Division of Cancer MedicineThe University of Texas M. D. Anderson Cancer Center, Unit 422HoustonUSA
  5. 5.Department of NeurologyMedical College of WisconsinMilwaukeeUSA

Personalised recommendations