The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QDx5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.

Purpose This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. Experimental Design Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated the drug without significant toxicities. Results Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response, 21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC (P = 0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy and change in tumor size (r = −0.38; P = 0.029). Conclusions Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be studied further.

Curcumin, in addition to its role as a spice, has been used for centuries to treat inflammatory disorders. Although the mechanism of action remains unclear, it has been shown to inhibit the activation of NF-κB and AP-1, transcription factors required for induction of many proinflammatory mediators. Due to its low toxicity it is currently under consideration as a broad anti-inflammatory, anti-tumor cell agent. In this study we investigated whether curcumin inhibited the response of γδ T cells to protease-resistant phosphorylated derivatives found in the cell wall of many pathogens. The results showed that curcumin levels ≥30 μM profoundly inhibited isopentenyl pyrophosphate-induced release of the chemokines macrophage inflammatory protein-1α and -1β and RANTES. Curcumin also blocked isopentenyl pyrophosphate-induced activation of NF-κB and AP-1. Commencing around 16 h, treatment with curcumin lead to the induction of cell death that could not be reversed by APC, IL-15, or IL-2. This cytotoxicity was associated with increased annexin V reactivity, nuclear expression of active caspase-3, cleavage of poly(ADP-ribose) polymerase, translocation of apoptosis-inducing factor to the nucleus, and morphological evidence of nuclear disintegration. However, curcumin led to only large scale DNA chromatolysis, as determined by a combination of TUNEL staining and pulse-field and agarose gel electrophoresis, suggesting a predominantly apoptosis-inducing factor-mediated cell death process. We conclude that γδ T cells activated by these ubiquitous Ags are highly sensitive to curcumin, and that this effect may contribute to the anti-inflammatory properties of this compound.

Human γδ T cells expressing the Vγ9Vδ2 gene segments are activated polyclonally by phosphoantigens found on a wide variety of pathogenic organisms. After ligand exposure, Vγ9Vδ2 T cells proliferate and rapidly secrete large amounts of cytokines and chemokines that contribute to the innate immune response to these pathogens. Neither APCs nor costimulatory molecules are required. In this study we examined whether these phosphoantigens activate protein kinase Cθ (PKCθ). This novel PKC isoform is essential for Ag signaling through the αβ TCR in a costimulation-dependent fashion. The results showed that isopentenyl pyrophosphate (IPP), a soluble phospholigand released by mycobacteria, led to the rapid and persistent activation of PKCθ in γδ T cells, as determined by evidence of translocation and phosphorylation. In contrast, no ligand-dependent response was detected for PKCα/β or PKCδ. Using the inhibitors Gö6976 and rottlerin, a role for both conventional and novel PKC isoforms in IPP-induced proliferation, CD25 expression, and cytokine and chemokine production was demonstrated. Gel-shift assays indicated that the transcription factors NF-κB and AP-1 were downstream targets of PKC activation. IPP also induced the rapid and persistent phosphorylation of extracellular signal-regulated kinases 1 and 2, p38 mitogen-activated kinase, and stress-activated kinase/c-Jun N-terminal kinase, but only an inhibitor of conventional PKCs blocked these responses. We conclude that the γδ T cell response to phosphoantigens is regulated by both novel and conventional PKC isoforms, with PKCθ being more responsive to ligand stimulation and PKCα/β to growth-factor availability.

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