Studies by several investigators have shown that 12-0-tetradecanoylphorbol-13-acetate (TPA) is an extraordinarily potent stimulator of differentiation of cultured human promyelocytic leukemia cells in vitro. In the present study, TPA was administered to humans by i.v. infusion without irreversible toxicity, and it was shown to have pharmacological activity for the treatment of myelocytic leukemia in patients refractory to cytosine arabinoside (Ara C), retinoic acid, and other antileukemic drugs. Marked decreases in bone marrow myeloblasts as well as temporary remission of disease symptoms were observed when TPA was administered alone or in combination with vitamin D 3 and Ara C. Additional studies with TPA after the determination of optimum dosing regimens are needed to determine whether long-lasting or permanent remissions of myelocytic leukemia can be achieved. Transient and reversible side effects were observed after a 1-mg i.v. dose of TPA, but these adverse effects became less intense or disappeared when a lower dose of TPA was used. The results of this study indicate a therapeutic effect of TPA in patients with myelocytic leukemia.

Abstract. σ k -Yamabe equations are conformally invariant equations generalizing the classical Yamabe equation. In [38] YanYan Li proved that an admissible solution with an isolated singularity at 0 ∈ R n to the σ k -Yamabe equation is asymptotically radially symmetric. In this work we prove that an admissible solution with an isolated singularity at 0 ∈ R n to the σ k -Yamabe equation is asymptotic to a radial solution to the same equation on R n \ {0}. These results generalize earlier pioneering work in this direction on the classical Yamabe equation by Caffarelli, Gidas, and Spruck. In extending the work of Caffarelli et al, we formulate and prove a general asymptotic approximation result for solutions to certain ODEs which include the case for scalar curvature and σ k curvature cases. An alternative proof is also provided using analysis of the linearized operators at the radial solutions, along the lines of approach in a work by Korevaar, Mazzeo, Pacard, and Schoen.

Fifty-two patients with solid tumors had depressed white blood cell and neutrophil counts because of prior treatment with cytotoxic cancer chemotherapeutic drugs. These patients were given one or more i.v. infusions of 0.125-0.25 mg of 12-O-tetradecanoylphorbol-13-acetate (TPA), and this treatment increased the low white blood cell and neutrophil counts toward the normal range. The average white blood cell and neutrophil counts were 2.55 ؋ 10 9 ͞liter and 1.76 ؋ 10 9 ͞liter, respectively, before treatment with TPA. After one or more i.v. infusions of TPA, the white blood cell and neutrophil counts increased to peak values of 5.92 ؋ 10 9 ͞liter and 4.76 ؋ 10 9 ͞liter, respectively, within a few days. Most patients had increased levels of white blood cells and neutrophils by 24 hr after a single i.v. infusion of 0.25 mg TPA. Elevated levels were observed for at least 3 days. This study demonstrates that treatment with parenteral TPA is feasible with useful biological activity. Only mild and reversible side effects were observed.12-O-Tetradecanoylphorbol-13-acetate (TPA) has a broad range of cellular and potentially useful pharmacological effects (1-3), but it was only recently studied in humans. In a pilot study, we found a therapeutic effect of intravenous infusions of TPA in patients with myelocytic leukemia who were refractory to other chemotherapeutic drugs (4). Myeloblasts in the bone marrow and peripheral blood were decreased, and several remissions were obtained (4). During the course of this earlier study in leukemia patients, we observed that TPA administration increased white blood cell (WBC) counts and neutrophils in several of the patients who previously had low WBC counts. Because granulocyte colony-stimulating factor (G-CSF) and granulocyte-monocyte colony-stimulating factor (GM-CSF) were not available to many patients, we obtained permission from the Central Hospital (Nan Yang, Henan) and the People's First Hospital of Nan Yang (Nan Yang, Henan) in the People's Republic of China to study the effects of i.v. infusions of TPA in patients who had low WBC counts because of prior treatment of solid tumors with one or more cytotoxic cancer chemotherapeutic drugs. In the present study, we show that i.v. infusion of TPA causes a rapid increase in WBC counts and neutrophils in the peripheral blood. METHODSTPA. Sterile ampules of TPA [0.25 or 0.5 mg in 2 ml of ethanol͞saline (65:35)] were prepared as described in our accompanying paper in this issue of the Proceedings (4). The ampules of TPA were supplied by Xichuan Pharmaceutical Co. (Nan Yang, Henan). Appropriate amounts of TPA were added to 200 ml of sterile saline for intravenous infusion. The intravenous infusion solutions were administered very slowly over a 1-hr interval.Peripheral Blood. Hemoglobin (Hb), WBC, red blood cells, neutrophils, lymphocytes, and platelets in peripheral blood were determined by routine clinical methods.Clinical Tests Used for Assessing Potential TPA Toxicity. Electrocardiogram evaluations were routinely undertaken, an...

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.

We consider the nonlinear Schrödinger equation on R N , N ≥ 1,with λ ∈ C and ℜλ > 0, for H 1 -subcritical nonlinearities, i.e. α > 0 and (N − 2)α < 4. Given a compact set K ⊂ R N , we construct H 1 solutions that are defined on (−T, 0) for some T > 0, and blow up on K at t = 0. The construction is based on an appropriate ansatz. The initial ansatz is simplywhere A ≥ 0 vanishes exactly on K, which is a solution of the ODE u ′ = λ|u| α u. We refine this ansatz inductively, using ODE techniques. We complete the proof by energy estimates and a compactness argument. This strategy is reminiscent of [3,4].