In vitro Anti-proliferative Effects of ProLindac™, a Novel Dach-Platinum-Linked Polymer Compound, as a Single Agent and in Combination with Other Anti-cancer Drugs

Abstract

ProLindac (AP5346) is a novel hydrophilic biocompatible co-polymer acting as a macromolecular carrier of bioactive DACH-platinum (Pt) complexes and has recently entered clinical trials. The pH-dependent polymer delivery system is intended to improve the safety profile of the DACH-Pt by exploiting the “leaky” nature of tumour angiogenesis, allowing for the possibility of high drug concentrations at the acidic hypoxic sites of the tumour. In our study, ProLindac displayed concentration- and time-dependent cytotoxic effects against a broad range of human cancer cell lines. The cytotoxicity profile, along with a number of preclinical experiments, showed cellular and molecular effects of ProLindac closely related to oxaliplatin, but different from cisplatin. We observed that expression of several genes of the DNA repair mechanism and the drug metabolism (MLH1, MDR1, GSTP1) seem to correlate with ProLindac cytotoxicity in a panel of human cancer cell lines. Exposure to 120 μM ProLindac (300 ng/mL Pt) led to incorporation of ~0.1 μg Pt per mg of DNA. Similar to that of oxaliplatin, ProLindac induced p21 expression and 48-exposure to IC₅₀ concentrations of ProLindac led to the accumulation of cells in the G2/M phase of cell cycle and apoptosis induction in p53-mutated HT29, as well as in wild-type p53 HCT116. In summary, ProLindac displayed molecular and cellular effects similar to that of oxaliplatin in most cancer cell lines.