Administration of a phorbol ester to patients with hematological malignancies: preliminary results from a phase I clinical trial of 12-O-tetradecanoylphorbol-13-acetate.
OBJECTIVE
Phorbol esters are capable of inducing a broad range of cellular effects,including the maturation/differentiation of hematopoietic cell lines (E. Huberman and M. F. Callaham, Proc. Natl. Acad. Sci. USA, 76: 1293-1297, 1979; J. Lotem and L. Sachs, Proc. Natl. Acad. Sci. USA, 76: 5158-5162, 1979; G. Rovera et al., Proc. Natl. Acad. Sci. USA, 76: 2779-2783, 1979; H. P. Koeffler, J. Clin. Investig., 66: 1101-1108, 1980). The ability to induce this differentiation at very low concentrations stimulated investigators to administer a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), to patients with myeloid leukemias in the People's Republic of China (Z. T. Han et al., Proc. Natl. Acad. Sci. USA, 95: 5357-5361, 1998). The tolerability of this therapy in China prompted Phase I studies of TPA in the United States. The purpose of this report is to demonstrate the tolerance of TPA at doses that result in detectable biological activity in blood and malignant cells.


METHODS
TPA was administered to patients with relapsed/refractory hematological malignancies.


RESULTS
Phenotypic effects were detected in malignant cells and TPA-associated biological activity was present in blood for up to several hours after the infusion.


CONCLUSIONS
These studies confirm the feasibility of TPA administration to humans and establish the foundation for the development of phorbol esters as therapy for patients with a variety of malignant and nonmalignant disorders.
Strair
Roger K
RK
The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08901, USA.
Schaar
Dale
D
Goodell
Lauri
L
Aisner
Joseph
J
Chin
Khew-Voon
KV
Eid
Joseph
J
Senzon
Rachelle
R
Cui
Xiao Xing
XX
Han
Zheng Tao
ZT
Knox
Beth
B
Rabson
Arnold B
AB
Chang
Richard
R
Conney
Allan
A
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D018922:HL-60 Cells; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
D018076:DNA, Complementary; D013755:Tetradecanoylphorbol Acetate