Overcoming biochemical pharmacologic mechanisms of platinum resistance with a texaphyrin–platinum conjugate

Abstract

In our effort to investigate further texaphyrin conjugation as a means of increasing delivery and accumulation of known anticancer platinum agents in cancer cells, we have continued our studies on the mode of action of a texaphyrin-platinum conjugate, particularly in cisplatin-resistant tumor cells that are characterized by several mechanisms of resistance, including reduced drug accumulation. Our results provide support for the proposal that intracellular platinum and Pt-DNA adduct levels were significantly increased using our conjugate relative to corresponding Pt controls. Moreover, no differences were found in cellular accumulation and Pt-DNA adduct formation between Pt sensitive and Pt resistant ovarian cells. As a result, resistance to the conjugate was lower than cisplatin in resistant cells. Based on these results we conclude that texaphyrin conjugation provides a promising strategy for overcoming biochemical pharmacologic mechanisms of resistance.

A texaphyrin–oxaliplatin conjugate that overcomes both pharmacologic and molecular mechanisms of cisplatin resistance in cancer cells

“…6 demonstrate that resistant 2780CP cells require 10-fold greater adduct levels as compared to A2780 cells for equivalent antiproliferative activity. As reported prevously, 19 cisplatin resistant 2780CP cells were capable of similarly tolerating ca. 10-fold the number of Pt–DNA lesions formed by conjugate 2 .…”

“…1) that produced equivalent levels of intracellular Pt and DNA–Pt adducts in both sensitive A2780 and isogenic multifactorial-resistant 2780CP cells upon exposure to conjugate 2 . 18,19 This conjugate was designed to form qualitatively identical adducts to those induced by cisplatin or carboplatin. 18 Consequently, it displayed potent cytotoxicity in the A2780 human ovarian tumor model.…”

“…However, conjugate was found to react more quickly than the clinically approved agent carboplatin ( t 1/2 = 36–45 hours) and conjugate 2 ( t 1/2 = 16 hours). 19,23 …”

“…14–17 That the effective delivery of Pt is due to the conjugating texaphyrin carrier and not the DACH–Pt moiety can be inferred from the knowledge that uptake and DNA adduct data with oxaliTEX (conjugate 3 ) mirror those reported by us for cisTEX (conjugate 2 ), which has an alternate diamine-Pt coordination environment. 19 …”

Recent Developments in Texaphyrin Chemistry and Drug Discovery

“…52-55 Cisplatin and carboplatin, however, are the main agents used in ovarian cancer. 56 The mode of action of platinum based agents is the formation of platinum-DNA adducts, which in turn activate several signal transduction pathways eventually leading to apoptosis. In several cell lines, platinum resistance has become a major factor, recapitulating a key limitation in terms of the clinical use of platinum-based drugs.…”