Phase I study of phenylacetate administered twice daily to patients with cancer

Abstract

Background. The growth‐inhibiting and differentiating effects of sodium phenylacetate against hematopoietic and solid tumor cell lines has aroused clinical interest in its use as an anticancer drug. In an earlier Phase I trial of phenylacetate aimed at maintaining serum drug concentrations in the range that proved active in vitro (>250 μg/ml) for 2 consecutive weeks, infusion rates approached the maximum velocity of drug elimination and commonly resulted in drug accumulation and reversible dose‐limiting neurologic toxicity. In this study, the authors described the nonlinear pharmacokinetics, metabolism, toxicity, and clinical activity of phenylacetate. Methods. The treatment regimen of this Phase I study was designed to expose patients intermittently to drug concentrations exceeding 250 μg/ml and to allow time for drug elimination to occur between doses to minimize accumulation. Sodium phenylacetate was administered as a 1‐hour infusion twice daily (8 a.m., 5 p.m.) at two dose levels of 125 and 150 mg/kg for a 2‐week period. Therapy was repeated at 4‐week intervals for patients who did not experience dose‐limiting toxicity or disease progression. Results. Eighteen patients (4 of whom previously were treated with phenylacetate by continuous intravenous infusion) received 27 cycles of therapy. Detailed pharmacokinetic studies for eight patients indicated that phenylacetate induced its own clearance by a factor of 27% in a 2‐week period. Dose‐limiting toxicity, consisting of reversible central nervous system depression, was observed for three patients at the second dose level. One patient with refractory malignant glioma had a partial response, and one with hormone‐independent prostate cancer achieved a 50% decline in prostate specific antigen level, which was maintained for 1 month. Conclusions. Phenylacetate administered at a dose of 125 mg/kg twice daily for 2 consecutive weeks is well tolerated. High grade gliomas and advanced prostate cancer are reasonable targets for Phase II clinical trials. Cancer 1995;75:2932–8.

Simvastatin induces apoptosis of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and delays development of EBV lymphomas

“…Simvastatin had an adjuvant effect in some, but not all, studies when given with other antitumor drugs (40,41). The plasma levels of statins achieved in humans in clinical trials (2.32 Ϯ 1.27 M at peak concentration) (45) were comparable to the concentration of simvastatin (2 M) that induced apoptosis of EBV-transformed LCLs in vitro and did not result in severe drug toxicity in the patients (30). Although a high dose of simvastatin was used in mice in this study (250 mg/kg͞day), administration of simvastatin to mice at 100-400 mg/kg͞day resulted in mean plasma drug levels about four to eight times higher than the mean human plasma drug level after an 80-mg oral dose, which is the maximum dose for cholesterollowering effects (46).…”

15-Lipoxygenase-2 (15-LOX-2) Is Expressed in Benign Prostatic Epithelium and Reduced in Prostate Adenocarcinoma

“…28 -31 This is a particularly intriguing hypothesis in light of the evidence that the synthetic activators of PPAR, the aromatic fatty acids phenyl acetate and phenyl butyrate, inhibit prostate cancer cell line growth in vitro and show activity against hormone-insensitive prostate cancer in vivo. [32][33][34] More recently, Kubota et al 35 demonstrated expression of PPAR␥ in PC-3, DU-145, and LNCaP cells and inhibition of PC-3 cell proliferation by PPAR␥ ligands, including the thiazolidinedione troglitazone and 15-deoxy-⌬ 12,14 -prostaglandin J 2 . The recent demonstration of activation of PPAR␥-dependent transcription by a variety of oxidized lipids, including specifically 15-HETE, 36 suggests a possible role of reduced 15-HETE activation of PPAR␥ in prostate carcinogenesis or progression.…”

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

“…19,36,57,81,[105][106][107][108][109][110][111] Thus, despite the prevalence of HMG-CoA reductase in all cells, data to date suggests statins will possess a high therapeutic index (efficacy/toxicity) when used to target apoptosis-sensitive tumor sub-types in vivo.…”

“…Dose-related toxicities were minimal and consisted of gastrointestinal dysfunction, and musculoskeletal system complaints including mylagias and muscle weakness. 109 Supplementation…”