Single intratumoral injection of long-acting benzyl ester of D-penicillamine inhibits the growth of melanoma tumor in mice

Abstract

Using a murine model of melanoma we tested the effect of D-penicillamine administered in repetitive, daily injections, or as a single large dose injected either in saline or in a biodegradable polymer. We also studied the effect of a single intratumoral injection of benzyl-ester-D-penicillamine on the growth of the tumor. Daily injections of the drug or its administration in a polymer or benzyl-ester of D-penicillamine were all significantly inhibitory. The inhibitory effect manifested 4-5 days after injection. The inhibition lasted 8-10 days. There was no evidence of local or systemic toxicity and no changes in body weight. Several possible mechanisms for the inhibitory effect are presented.

d-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis

“…It has been demonstrated before that intratumoral injection of a long-acting benzyl ester of D-penicillamine inhibits the growth of melanoma tumors in mice [52]. In our murine SCID A375 melanoma model, significant inhibition of tumor growth was observed upon systemic administration of DP at very high daily doses (i.p.…”

Enhanced Intracellular Delivery of the Reactive Oxygen Species (ROS)-Generating Copper Chelator D-Penicillamine via a Novel Gelatin−D-Penicillamine Conjugate

“…We have previously reported on a novel D-pen-nanoparticle formulation for metal chelation therapy . Also, Chvapil et al recently reported on the synthesis of a hexyl-D-pen-ester that converted D-pen to a more lipophilic form (Log P = 1.61) , . The ester prodrug strategy for D-pen delivery could potentially have problems such as (i) the lack of protection of the critical thiol group and (ii) the slow rate of D-pen release from the lipophilic ester prodrug.…”