CORRESPONDENCE

Re: Therapeutic Targeting of Transcription in Acute Promyelocytic Leukemia by Use of an Inhibitor of Histone Deacetylase

Dvorit Samid

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 phenylbutyrate—the 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.Go



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Fig. 1. Combination treatments involving phenylbutyrate.

 
Based on these findings, the benefit of combining phenylbutyrate with retinoids or cytotoxic drugs could be extended to solid tumors. By reducing the production of angiogenic factors such as basic fibroblast growth factor (with no toxicity to endothelial cells), phenylbutyrate might also enhance the activity of interferons and, possibly, other anti-angiogenic agents. Increases in antigenicity with declines in tumor-mediated immunosuppression (phenylbutyrate increases the expression of class-I major histocompatibility antigens and reduces the secretion of transforming growth factor ß2) indicate that this aromatic fatty acid could convert neoplasms into better targets for immunotherapy. Finally, reduction in antioxidant capacity, which enhances free-radical mediated cell damage, suggests that phenylbutyrate may serve as a potentially useful radiosensitizer (4). Considering its novel mechanisms of action and low toxicity profile (5-7), the clinical investigation of combination therapies with phenylbutyrate is warranted.

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.[Abstract/Free Full Text]

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.


 

RESPONSE

Raymond P. Warrell, Jr.

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-{alpha} promyelocytic leukemia cells that had acquired retinoid resistance as well as differentiate PLZF/RAR-{alpha} 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{alpha} and PLZF-RAR{alpha} 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-{alpha} 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.[Abstract/Free Full Text]

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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