In vitro Antitumor Activity, Intracellular Accumulation, and DNA Adduct Formation of cis‐[((1R, 2R)‐1,2‐Cyclohexanediamine‐N, N')bis(myristato)] Platinum (II) Suspended in Lipiodol

Abstract

SM-11355, cis-[((1R,2R)-1,2-cyclohexanediamine-N,N′ ′ ′ ′)bis(myristato)] platinum (II), is a lipophilicplatinum complex under clinical development that targets primary hepatocellular carcinoma using Lipiodol as a carrier. SM-11355 was compared with cisplatin (CDDP) using an in vitro evaluation system capable of examining the release characteristics and the cytotoxicity of drugs suspended in Lipiodol. SM-11355 suspended in Lipiodol (SM-11355/Lipiodol) and CDDP suspended in Lipiodol (CDDP/Lipiodol) showed cytotoxic activity against rat ascites hepatoma AH-109A cells in a dosedependent manner. Their IC 50 values following 7-day exposure were 22.3 and 0.40 µ µ µ µg/ml, respectively. Following the subsequent 7-day exposure, from day 7 to day 14 after preparation of the suspension, SM-11355/Lipiodol showed an almost equivalent activity, but CDDP/Lipiodol did not show any activity at all. SM-11355/Lipiodol showed a sustained release into the culture medium over the course of a 14-day exposure. Following the exposure to CDDP/Lipiodol, the platinum concentration in the medium was at its maximum on the first day and remained constant thereafter. Intracellular platinum uptake and formation of platinum-DNA adducts were dependent on the release characteristics of each drug suspension. For SM-11355/Lipiodol, the drug release, intracellular drug uptake, and formation of platinum-DNA adducts over the course of the subsequent 7-day exposure were similar to those observed during the first 7 days. DPC, one of the compounds released from SM-11355/Lipiodol, was taken up by cells and showed formation of platinum-DNA adducts. Thus, this study suggests that SM-11355/Lipiodol may release active platinum compound(s) that bind to nuclear DNA and mediate the cytotoxic activity of SM-11355/Lipiodol.Key words: Lipiodol -Cisplatin -Hepatocellular carcinoma -Sustained release Primary hepatocellular carcinoma therapy has improved as a result of advances made in hepatic arterial infusion chemotherapy.1-3) As Lipiodol, an oily lymphographic agent, is selectively retained in hepatic tumor tissue when injected into the hepatic artery, it has been used both in the diagnosis and therapy of hepatic cancer. 4) Numerous studies have reported that Lipiodol selectively delivers various antitumor drugs to tumors. 5-9) SMANCS, amphipathic polymer styrene maleic acid neocarzinostatin, was developed as an anticancer drug for use in this therapy. 5, 10-12)The widespread clinical use of SMANCS has revealed areas of effectiveness and a few problems. CDDP, cisplatin, is reportedly highly effective against various carcinomas, and when suspended in Lipiodol (CDDP/Lipiodol) is effective against hepatocellular carcinoma. 7, 13) However, therapeutic problems associated with CDDP/Lipiodol include an insufficient anticancer effect and adverse effects resulting from both inadequate stability of the suspension and rapid release of the drug.SM-11355 has been developed as a lipophilic platinum complex that has the added feature of lipophilicity, which makes this anticancer...

Preparation, Characterization, and Antitumor Activities of Miriplatin-Loaded Liposomes

“…The commonly used quantitative methods for platinum-containing formulations are inductively coupled plasma mass spectrometry 24 and flameless atomic absorption spectrophotometry 25 ; both are not convenient as HPLC. Although the limit of detection of HPLC is usually lower than that of inductively coupled plasma mass spectrometry and flameless atomic absorption spectrophotometry, HPLC is adequate for the routine quality control of lipomiriplatins.…”

Continuous Exposure to Low-Dose Cisplatin and Apoptosis

“…We have previously used rat ascites hepatoma AH-109A cells to assess the effect of a sustained release preparation for the treatment of liver cancer. 14,17,18) In those studies, we found that continuous exposure to a CDDP derivative causes a dose-dependent elevation of intracellular and DNA-bound platinum in AH-109A cells. In the current study we compared the ability various dosing regimens, including a single exposure and multiple exposures, to induce apoptosis.…”

“…11,12) For this reason, sustained release formulations of CDDP or CDDP derivatives have been developed. [13][14][15][16] However, it has not been clear whether continuous exposure with low-dose CDDP can induce apoptosis as effectively as a single high-dose exposure CDDP.We therefore compared the ability of CDDP to induce apoptosis when delivered as a single high-dose exposure or as multiple low-dose exposures. In these studies, the induction of apoptosis was assessed by measuring caspase-3 activity, DNA fragmentation, and the percent of cells in the sub-G1 phase.…”

“…11,12) For this reason, sustained release formulations of CDDP or CDDP derivatives have been developed. [13][14][15][16] However, it has not been clear whether continuous exposure with low-dose CDDP can induce apoptosis as effectively as a single high-dose exposure CDDP.…”

Cytotoxicity of cis‐[((1R,2R)‐1,2‐Cyclohexanediamine‐N,N')bis(myristato)]‐platinum (II) Suspended in Lipiodol in a Newly Established Cisplatinresistant Rat Hepatoma Cell Line

“…It has been reported that CDDP-resistant cell lines exhibit no cross-resistance with platinum complexes containing different carrier ligands. [22][23][24][25] Thus, SM-11355/Lipiodol can be expected to show sufficient antitumor activity in CDDP-resistant hepatic tumors.…”