Clinical pharmacology of UCN-01: Initial observations and comparison to preclinical models

Abstract

UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2-0.3 microM. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T1/2. Specific binding to human alpha1-acidic glycoprotein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in "real time" with phase I studies.

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

“…Such clinical testing has been complicated by the fact that indolocarbazoles such as UCN-01 (i.e., 7-hydroxystaurosporine) can bind with high affinity to the abundant serum protein human alpha-1 acidic glycoprotein (AGP). 16 In this regard, while the IC 50 value for inhibition of purified Trks A-C in aqueous buffer is ~5 nM the IC 50 for inhibition of purified Trks in human plasma ranges between 900-2600 ng/ml (2100-6200 nM) (unpublished data). While total concentration of CEP-701 can be measured via HPLC analysis, assays for free concentration of CEP-701 are not available.…”

Molecular signals in anti-apoptotic survival pathways

“…224,225 PKC inhibitors under clinical evaluation include UCN-01 and PKC412. 226,227 The PKC inhibitor LY333531 specifically targets PKC ␤ and has successfully demonstrated anti-tumorigenic activity in preclinical trials. 228 Although Bcl-2 antisense treatment has demonstrated significant anti-apoptotic effects, 229 the lack of a specific biochemical inhibitor is limiting clinical investigation.…”

Small molecule modulators of cyclin-dependent kinases for cancer therapy

“…Unique clinical features observed in this initial human experience included an unexpected very prolonged half-life (*600 h), 100 times longer than the half-life observed in preclinical models, probably to a very avid binding to the human plasma protein alpha-1-acid glycoprotein (AGP) Sausville et al, 1998). Dose limiting toxicities were nausea/ vomiting, symptomatic hyperglycemia and pulmonary toxicity.…”