A phase I clinical trial of 12- O-tetradecanoylphorbol-13-acetate for patients with relapsed/refractory malignancies

Abstract

Phorbol esters activate protein kinase C and modulate a variety of downstream cell signaling pathways. 12-O-tetradecanoylphorbol-13-acetate (TPA) is a phorbol ester that induces differentiation or apoptosis in a variety of cell lines at low concentrations. A phase I dose escalation trial of TPA was undertaken for patients with relapsed or refractory malignancies. The starting dose was 0.063 mg/m2 and most patients were treated with an intravenous infusion of TPA on days 1-5 and 8-12 followed by a 2-week rest period prior to retreatment. Thirty-five patients were treated. A biological assay was used to monitor levels of TPA-like activity in the blood after treatment. Serious adverse events included individual episodes of gross hematuria, a grand mal seizure, syncope, and hypotension. Many patients had transient fatigue, mild dyspnea, fever, rigors, and muscular aches shortly after the infusion. Dose-limiting toxicities included syncope and hypotension at a dose of 0.188 mg/m2. Only a single patient had evidence of tumor response. These studies establish 0.125 mg/m2 as the maximally tolerated dose when TPA is administered on this schedule.

Effects of 12-O-Tetradecanoylphorbol-13-acetate (TPA) in Combination with Paclitaxel (Taxol) on Prostate Cancer LNCaP Cells Cultured In vitro or Grown as Xenograft Tumors in Immunodeficient Mice

“…infusions of TPA increased the number of circulating WBC and neutrophils in patients with depressed bone marrow caused by prior treatment with cytotoxic chemotherapeutic drugs (2). The results obtained in both studies and data from a phase I trial with TPA at the Cancer Institute of New Jersey in New Brunswick (3,4) indicated an acceptable toxicity profile. In cell culture studies, a low clinically achievable concentration of TPA (0.16 nmol/L) in combination with clinically achievable concentrations of all-trans retinoic acid (0.1-1 Amol/L), 1a,25-dihydroxyvitamin D 3 (1 nmol/L), or sodium butyrate (100 Amol/L) synergistically inhibited the growth and stimulated the differentiation of cultured HL-60 myeloid leukemia cells, suggesting that combinations of these drugs may be more effective than TPA alone for the treatment of refractory myeloid leukemia patients (5).…”

“…Our earlier study showed that the peak blood concentrations of TPA F SD in several patients who received an i.v. infusion of TPA (0.125 mg/m 2 ) was 1.75 F 0.55 ng/mL and ranged between 0.3 and 5.2 ng/mL (4,23). Our recent study showed that the peak blood level of TPA after a 100 ng/g body weight injection was f1 ng/mL (13).…”

“…Although treatment of LNCaP cells with a low concentration of TPA or paclitaxel alone had only a modest effect on apoptosis, treatment of the cells with a combination of these two agents resulted in a greater than additive increase in apoptotic cells (Table 1). The concentrations of TPA used to obtain synergistic effects on cell growth (0.2-1 ng/mL) are clinically achievable (4,23). Our earlier study showed that the peak blood concentrations of TPA F SD in several patients who received an i.v.…”

Nanomechanical measurement of adhesion and migration of leukemia cells with phorbol 12-myristate 13-acetate treatment

“…43 Therefore, accurately knowing the interaction forces between cells and cell-proteins would allow better comprehension of the potential therapeutic effect of drug candidates. 44 However, many agents, such as the PMA studied here, which was used in clinical trials for hematologic malignancy, 45,46 are activators in the signaling transduction pathway of PKC, 47 which can affect not only the adhesion and migration behavior of cells but also their proliferation, differentiation, and death. For such agents, the conventional batch-cell adhesion assays (such as that shown in Figure 1), may not give a precise indication of the intrinsic cell adhesion and hence metastatic potential, since cell proliferation is also affected by the treatment and the cell adhesion may be affected by the trypsinization.…”

Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of aplysiatoxin with anti-proliferative and cytotoxic activities

“…However, difficulties are associated with their application to therapeutic uses due to their potent tumor-promoting and inflammatory activities. 7,8) Bryostatin-1 (bryo-1) 9) which was isolated from the marine bryozoan Bugula neritina, is a unique PKC activator that does not exhibit tumor-promoting or inflammatory activity. Bryo-1 has been reported to have significant anti-cancer and anti-proliferative activities, and these have been attributed to activation of the PKCδ isozyme, [10][11][12] which plays a tumor suppressor role and is involved in apoptosis.…”