Phase I toxicity and pharmacology study of trimethylcolchicinic acid in patients with advanced malignancies

Abstract

A phase I study of trimethylcolchicinic acid (TMCA) given orally once daily for 5 days every 3rd week was performed in 19 patients with advanced malignancies. Myelosuppression and mucositis were the major toxicities observed. Serum TMCA levels were monitored and appear to be useful in predicting toxicities. A partial response was seen in one lymphoma patient and stabilization of disease was noted in one patient each with prostatic and ovarian cancer.

A Phase II Trial of Oral Trimethylcolchicinic Acid in Patients with Hormone Refractory Prostate Cancer

“…Previously described pharmacokinetic parameters were redefined. The mean plasma T 1/2 of 10.7 hr confirmed that seen in another study (10). The clearance and volume of distribution, however, differed by a factor of 2–4.…”

“…Data were fit to a one‐compartment model with first‐order absorption and elimination. Previously published parameters were used as initial estimates for the population model (10). Estimates of the volume of distribution (V d ), clearance (CL), and absorption rate constant (K a ) for each individual were determined by a maximum a priori Bayesian method.…”

“…Under the assumption that a different dosing schedule might prove useful in decreasing toxicity while maintaining or increasing efficacy, Hu et al (10) more recently performed a Phase I toxicity and pharmacology study of TMCA. Patients received 5-7 mg/m 2 TMCA daily for 5 days with cycles repeated every 3 weeks.…”

Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin a-4 phosphate

“…The mechanism by which CA4P and CA4 act on pathologic neovasculature is not completely understood; although it appears that through its reversible binding to tubulin, CA4P causes distortion and detachment of immature proliferating endothelial cells in abnormal vasculature (mature endothelial cell shape is maintained by the secondary scaffolding protein actin). Because of its reversible effects and the short half-life of about 10-27 min, as demonstrated in animal studies, CA4P does not display the side effects typical of tubulin binding inhibitors [1]. Although it is a vascular targeted agent, its specific mechanism of action and side effect profile differ from those of vascular endothelial growth factor (VEGF) inhibitors [2].…”

Antineoplastic tropolone derivatives as useful biomarkers: fluorescence enhancement upon binding to biological targets

“…6 Colchicine (COL) and analogues such as colcemid (COD), deacetylcolchicine (DCOL), colchiceine (CEI) and deacetylcolchiceine (DCEI) are antimitotic drugs with important anticancer effects but its clinical usefulness is limited by severe toxicities. [7][8][9] Their structure contains a tropolone moiety (C ring), in addition to a trimethoxybenzene ring (A ring) and a sevenmembered ring (B ring, see Scheme 1). 10 The binding of these drugs to tubulin is the basis for antineoplastic behavior via interrupted mitosis, 7 and it is accompanied by a marked enhancement of the fluorescence.…”