Correspondence to: Dvorit Samid, Ph.D., Department of Medicine, University of Virginia Health Sciences Center, Jordan Annex, Box 513, Lane Rd., Rm. 2229, Charlottsville, VA 22908.
The study by Warrell et al. (1) of a complete cytogenetic remission in a patient with refractory acute promyelocytic leukemia following treatment with all-trans-retinoic acid and phenylbutyratethe differentiating aromatic fatty acid currently being developed by the National Cancer Institute (NCI)provides the first clinical demonstration that combination differentiation therapy may represent an important therapeutic advance. Discussing the implications of their results, the authors proposed that phenylbutyrate might have restored sensitivity to the antileukemic effect of all-trans-retinoic acid by inducing hyperacetylation of DNA-associated histones, a process known to facilitate gene transcription.
In this respect, preclinical studies (2,3) initiated at the NCI in 1991
have established that, in addition to inhibiting histone deacetylases, aromatic fatty acids (and
phenylbutyrate in particular) can remove transcriptional repression also by inhibiting DNA
methylation and by activating peroxisome proliferator-activated receptors, which are
transcriptional factors of the nuclear receptor superfamily. The observed changes in gene
expression and tumor biology provide a scientific rationale for the design of a variety of
combination treatment strategies in addition to that used by Warrell et al. Examples of synergistic
antitumor activity noted in experimental models are shown in Fig. 1.
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REFERENCES
1
Warrell RP Jr, He LZ, Richon V, Calleja E, Pandolfi PP.
Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of
histone deacetylase. J Natl Cancer Inst 1998;90:1621-5.
2 Samid D, Shack S, Sherman LT. Phenylacetate: a novel nontoxic inducer of tumor cell differentiation. Cancer Res 1992;52:1988-92.[Abstract]
3 Samid D, Hudgins WR, Shack S, Liu L, Prasanna P, Myers CE. Phenylacetate and phenylbutyrate as novel, nontoxic differentiation inducers. Adv Exp Med Biol 1997;400A:501-5.
4 Miller AC, Whittaker T, Thibault A, Samid D. Modulation of radiation response of human tumour cells by the differentiation inducers, phenylacetate and phenylbutyrate. Int J Radiat Biol 1997;72:211-8. [Medline]
5 Thibault A, Figg WD, Samid D. A phase I study of the differentiating agent phenylbutyrate in patents with cancer abstract. Proc ASCO 1996;15:A1539.
6 Carducci M, Bowling MK, Eisenberger M, Sinibaldi V, Chen T, Noe D, et al. Phenylbutyrate (PB) for refractory solid tumors: phase I clinical and pharmacological evaluation of intravenous and oral PB. Anticancer Res 1997;17:3972-3.
7 Gore SD, Miller CB, Weng LJ, Burks K, Griffin CA, Chen TOL, et al. Clinical development of sodium phenylbutyrate (SPB) as a putative differentiating agent in myeloid malignancies. Anticancer Res 1997;17:3981-2.
Correspondence to: Raymond P. Warrell, Jr., M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.
Dr. Samid, who has been a leader in the investigation of aromatic
fatty acids, correctly notes that phenylbutyrate has a number of
biochemical effects other than inhibition of histone deacetylase
(HDAC). Our interest in the drug was prompted by observations from our
group (1) and others (2,3) that trichostatin A, a
potent HDAC inhibitor, could both restore sensitivity to
all-trans-retinoic acid (RA) in PML/RAR- promyelocytic
leukemia cells that had acquired retinoid resistance as well as
differentiate PLZF/RAR-
leukemic cells that are inherently RA
insensitive. Phenylbutyrate is markedly less potent relative to other
HDAC inhibitors (4,5). Nonetheless, we found that histone
hyperacetylation can be detected in target cells in vivo, and
that this effect can be reproducibly induced by concentrations of
phenylbutyrate that are well tolerated. As noted by Dr. Samid, the drug
synergizes with a number of agents, and it may be useful in diseases
for which an acetylation process has not yet been characterized. We
agree that these leads should be pursued in clinical studies.
REFERENCES
1
He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, et
al. Distinct interactions of PML-RAR and PLZF-RAR
with co-repressors determine
differential responses to RA in APL. Nat Genet 1998;18:126-35.[Medline]
2 Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 1998;391:811-4.[Medline]
3
Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V,
Cioce M, et al. Fusion proteins of the retinoic acid receptor- recruit histone deacetylase in
promyelocytic leukaemia. Nature 1998;391:815-8.[Medline]
4
Kwon HJ, Owa T, Hassig CA, Shimada J, Schreiber SL.
Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of
histone deacetylase. Proc Natl Acad Sci U S A 1998;95:3356-61.
5 Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S. FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 1998;241:126-33.[Medline]
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