Limits...
Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of tumors implanted in rat livers by inducing platinum-DNA adducts to form and massive apoptosis.

Hanada M, Baba A, Tsutsumishita Y, Noguchi T, Yamaoka T, Chiba N, Nishikaku F - Cancer Chemother. Pharmacol. (2008)

Bottom Line: Dichloro[(1R, 2R)-1, 2-cyclohexane diamine-N, N']platinum, the most abundant platinum compound released from miriplatin, was as effective as cisplatin in inhibiting the growth of cells.Miriplatin was selectively disposed of in tumors, maintained in tumors longer than cisplatin and caused apparent tumor regression inducing platinum-DNA adducts to form and massive apoptosis.Miriplatin appears to be a suitable chemotherapeutic agent for transarterial chemoembolization.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co, Ltd, Osaka, Japan. mitsuharu-hanada@ds-pharma.co.jp

ABSTRACT

Background: Miriplatin (formerly SM-11355), a novel lipophilic platinum complex developed to treat hepatocellular carcinoma, is administered into the hepatic artery using an oily lymphographic agent (Lipiodol Ultra-Fluide) as a carrier. We clarified the usefulness of miriplatin as an agent for transarterial chemoembolization.

Methods: Platinum compounds released from miriplatin into serum, medium and Earle's balanced salt solution were examined. Then, miriplatin and cisplatin were administered to rats bearing hepatoma AH109A tumors in livers. Platinum concentrations in tissues and DNA were assessed.

Results: Miriplatin showed a more sustained release than cisplatin. Dichloro[(1R, 2R)-1, 2-cyclohexane diamine-N, N']platinum, the most abundant platinum compound released from miriplatin, was as effective as cisplatin in inhibiting the growth of cells. Miriplatin was selectively disposed of in tumors, maintained in tumors longer than cisplatin and caused apparent tumor regression inducing platinum-DNA adducts to form and massive apoptosis.

Conclusion: Miriplatin appears to be a suitable chemotherapeutic agent for transarterial chemoembolization.

Show MeSH

Related in: MedlinePlus

In vitro cell growth inhibition by platinum compounds released from miriplatin/LPD. a Release characteristics of miriplatin/LPD and cisplatin/LPD into the culture medium. Aliquots (0.5 mL) of miriplatin/LPD (100 μg/mL, filled circle) and cisplatin/LPD (100 μg/mL, open circle) were added into Falcon cell culture inserts in wells containing 0.5 mL of RPMI 1640 medium supplemented with 10% FBS. The platinum concentrations in the medium were measured using FAAS. All results are given as the mean ± SD (n = 3 or 6). b The relation between platinum concentrations in the medium and cytotoxic activities following treatment with miriplatin/LPD and cisplatin/LPD. One day after the plating of cells into microplates, miriplatin/LPD and cisplatin/LPD were added into Falcon cell culture inserts. Cells were exposed to agents for 7 days at 37°C in 5% CO2. The platinum concentration was measured using FAAS. filled circle growth rates of cells treated with miriplatin, open circle growth rates of cells treated with cisplatin, filled square platinum concentrations in the medium after treatment with miriplatin, open square platinum concentrations in the medium after treatment with cisplatin. All results are given as the mean ± SD of triplicates. c HPLC/ICP-MS analysis of platinum compounds released from miriplatin/LPD. Three milliliters of miriplatin/LPD (20 mg/mL) was layered over 6 mL of Earle’s balanced salt solution supplemented with magnesium sulfate in test tubes. Test tubes were rotated vertically for 7 days at 5 rpm in an incubator at 37°C under protection from light. Platinum compounds in aqueous phase were analyzed by HPLC/ICP-MS
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2691803&req=5

Fig2: In vitro cell growth inhibition by platinum compounds released from miriplatin/LPD. a Release characteristics of miriplatin/LPD and cisplatin/LPD into the culture medium. Aliquots (0.5 mL) of miriplatin/LPD (100 μg/mL, filled circle) and cisplatin/LPD (100 μg/mL, open circle) were added into Falcon cell culture inserts in wells containing 0.5 mL of RPMI 1640 medium supplemented with 10% FBS. The platinum concentrations in the medium were measured using FAAS. All results are given as the mean ± SD (n = 3 or 6). b The relation between platinum concentrations in the medium and cytotoxic activities following treatment with miriplatin/LPD and cisplatin/LPD. One day after the plating of cells into microplates, miriplatin/LPD and cisplatin/LPD were added into Falcon cell culture inserts. Cells were exposed to agents for 7 days at 37°C in 5% CO2. The platinum concentration was measured using FAAS. filled circle growth rates of cells treated with miriplatin, open circle growth rates of cells treated with cisplatin, filled square platinum concentrations in the medium after treatment with miriplatin, open square platinum concentrations in the medium after treatment with cisplatin. All results are given as the mean ± SD of triplicates. c HPLC/ICP-MS analysis of platinum compounds released from miriplatin/LPD. Three milliliters of miriplatin/LPD (20 mg/mL) was layered over 6 mL of Earle’s balanced salt solution supplemented with magnesium sulfate in test tubes. Test tubes were rotated vertically for 7 days at 5 rpm in an incubator at 37°C under protection from light. Platinum compounds in aqueous phase were analyzed by HPLC/ICP-MS

Mentions: The release characteristics for miriplatin/LPD and cisplatin/LPD using cell culture inserts are shown in Fig. 2a. While the platinum concentrations in the medium treated with miriplatin/LPD gradually increased, depending on incubation time, for 7 days, cisplatin/LPD caused a rapid increase in the platinum concentrations in the medium within a day, with the concentration almost the same until day 7. Thus, miriplatin/LPD showed a more sustained release over 7 days than cisplatin/LPD. First, we examined in vitro antitumor effects of miriplatin/LPD and cisplatin/LPD using cell culture inserts. In this system, the LPD suspension does not make contact with the cells directly, but via membranes with tiny pores. IC50 values for rat ascite hepatoma AH109A cells after 7 days of exposure to miriplatin/LPD and cisplatin/LPD were 0.89 ± 015 and 0.14 ± 0.09 μg/mL, respectively. Increasing the concentrations of miriplatin and cisplatin in LPD increased the platinum concentrations in medium at day 7 (Fig. 2b). In addition, both agents inhibited cell growth depending on their concentrations in the medium. Antitumor platinum complexes undergo leaving group exchange prior to biotransformation. To determine which platinum compounds were generated from miriplatin/LPD, we examined those released into Earle’s balanced salt solution. This solution consists of inorganic ingredients similar to a culture medium or serum, but lacks glutathione, amino acids, and proteins which inactivate platinum complexes [33]. Figure 2c shows a representative chromatogram. After 7 days, only three platinum complexes; DPC, DPCI, and DPI were detected in aqueous solution. DPC was the most abundant of the three. These results show that biological nucleophiles including chloride can displace leaving groups of miriplatin at concentrations which occur in the culture medium or serum. Next, in vitro antitumor effects of miriplatin, cisplatin, and zinostatin stimalamer were examined in addition to those of DPC or DPI, both of which were detected as compounds released from miriplatin/LPD. IC50 values for AH109A cells after 3 days of exposure to DPC, DPI, cisplatin, and zinostatin stimalamer were 0.14 ± 0.07, 0.83 ± 0.32, 0.30 ± 0.07, and 0.13 ± 0.00 μg/mL, respectively. Miriplatin did not inhibit cell growth at the highest concentrations tested (20 μg/mL) probably due to its low water solubility. DPC was about six times more active than DPI, and as potent as cisplatin and zinostatin stimalamer (Fig. 3). From these results, it was shown that platinum compounds released from miriplatin/LPD, but not miriplatin itself, inhibited the growth of AH109A cells.Fig. 2


Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of tumors implanted in rat livers by inducing platinum-DNA adducts to form and massive apoptosis.

Hanada M, Baba A, Tsutsumishita Y, Noguchi T, Yamaoka T, Chiba N, Nishikaku F - Cancer Chemother. Pharmacol. (2008)

In vitro cell growth inhibition by platinum compounds released from miriplatin/LPD. a Release characteristics of miriplatin/LPD and cisplatin/LPD into the culture medium. Aliquots (0.5 mL) of miriplatin/LPD (100 μg/mL, filled circle) and cisplatin/LPD (100 μg/mL, open circle) were added into Falcon cell culture inserts in wells containing 0.5 mL of RPMI 1640 medium supplemented with 10% FBS. The platinum concentrations in the medium were measured using FAAS. All results are given as the mean ± SD (n = 3 or 6). b The relation between platinum concentrations in the medium and cytotoxic activities following treatment with miriplatin/LPD and cisplatin/LPD. One day after the plating of cells into microplates, miriplatin/LPD and cisplatin/LPD were added into Falcon cell culture inserts. Cells were exposed to agents for 7 days at 37°C in 5% CO2. The platinum concentration was measured using FAAS. filled circle growth rates of cells treated with miriplatin, open circle growth rates of cells treated with cisplatin, filled square platinum concentrations in the medium after treatment with miriplatin, open square platinum concentrations in the medium after treatment with cisplatin. All results are given as the mean ± SD of triplicates. c HPLC/ICP-MS analysis of platinum compounds released from miriplatin/LPD. Three milliliters of miriplatin/LPD (20 mg/mL) was layered over 6 mL of Earle’s balanced salt solution supplemented with magnesium sulfate in test tubes. Test tubes were rotated vertically for 7 days at 5 rpm in an incubator at 37°C under protection from light. Platinum compounds in aqueous phase were analyzed by HPLC/ICP-MS
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2691803&req=5

Fig2: In vitro cell growth inhibition by platinum compounds released from miriplatin/LPD. a Release characteristics of miriplatin/LPD and cisplatin/LPD into the culture medium. Aliquots (0.5 mL) of miriplatin/LPD (100 μg/mL, filled circle) and cisplatin/LPD (100 μg/mL, open circle) were added into Falcon cell culture inserts in wells containing 0.5 mL of RPMI 1640 medium supplemented with 10% FBS. The platinum concentrations in the medium were measured using FAAS. All results are given as the mean ± SD (n = 3 or 6). b The relation between platinum concentrations in the medium and cytotoxic activities following treatment with miriplatin/LPD and cisplatin/LPD. One day after the plating of cells into microplates, miriplatin/LPD and cisplatin/LPD were added into Falcon cell culture inserts. Cells were exposed to agents for 7 days at 37°C in 5% CO2. The platinum concentration was measured using FAAS. filled circle growth rates of cells treated with miriplatin, open circle growth rates of cells treated with cisplatin, filled square platinum concentrations in the medium after treatment with miriplatin, open square platinum concentrations in the medium after treatment with cisplatin. All results are given as the mean ± SD of triplicates. c HPLC/ICP-MS analysis of platinum compounds released from miriplatin/LPD. Three milliliters of miriplatin/LPD (20 mg/mL) was layered over 6 mL of Earle’s balanced salt solution supplemented with magnesium sulfate in test tubes. Test tubes were rotated vertically for 7 days at 5 rpm in an incubator at 37°C under protection from light. Platinum compounds in aqueous phase were analyzed by HPLC/ICP-MS
Mentions: The release characteristics for miriplatin/LPD and cisplatin/LPD using cell culture inserts are shown in Fig. 2a. While the platinum concentrations in the medium treated with miriplatin/LPD gradually increased, depending on incubation time, for 7 days, cisplatin/LPD caused a rapid increase in the platinum concentrations in the medium within a day, with the concentration almost the same until day 7. Thus, miriplatin/LPD showed a more sustained release over 7 days than cisplatin/LPD. First, we examined in vitro antitumor effects of miriplatin/LPD and cisplatin/LPD using cell culture inserts. In this system, the LPD suspension does not make contact with the cells directly, but via membranes with tiny pores. IC50 values for rat ascite hepatoma AH109A cells after 7 days of exposure to miriplatin/LPD and cisplatin/LPD were 0.89 ± 015 and 0.14 ± 0.09 μg/mL, respectively. Increasing the concentrations of miriplatin and cisplatin in LPD increased the platinum concentrations in medium at day 7 (Fig. 2b). In addition, both agents inhibited cell growth depending on their concentrations in the medium. Antitumor platinum complexes undergo leaving group exchange prior to biotransformation. To determine which platinum compounds were generated from miriplatin/LPD, we examined those released into Earle’s balanced salt solution. This solution consists of inorganic ingredients similar to a culture medium or serum, but lacks glutathione, amino acids, and proteins which inactivate platinum complexes [33]. Figure 2c shows a representative chromatogram. After 7 days, only three platinum complexes; DPC, DPCI, and DPI were detected in aqueous solution. DPC was the most abundant of the three. These results show that biological nucleophiles including chloride can displace leaving groups of miriplatin at concentrations which occur in the culture medium or serum. Next, in vitro antitumor effects of miriplatin, cisplatin, and zinostatin stimalamer were examined in addition to those of DPC or DPI, both of which were detected as compounds released from miriplatin/LPD. IC50 values for AH109A cells after 3 days of exposure to DPC, DPI, cisplatin, and zinostatin stimalamer were 0.14 ± 0.07, 0.83 ± 0.32, 0.30 ± 0.07, and 0.13 ± 0.00 μg/mL, respectively. Miriplatin did not inhibit cell growth at the highest concentrations tested (20 μg/mL) probably due to its low water solubility. DPC was about six times more active than DPI, and as potent as cisplatin and zinostatin stimalamer (Fig. 3). From these results, it was shown that platinum compounds released from miriplatin/LPD, but not miriplatin itself, inhibited the growth of AH109A cells.Fig. 2

Bottom Line: Dichloro[(1R, 2R)-1, 2-cyclohexane diamine-N, N']platinum, the most abundant platinum compound released from miriplatin, was as effective as cisplatin in inhibiting the growth of cells.Miriplatin was selectively disposed of in tumors, maintained in tumors longer than cisplatin and caused apparent tumor regression inducing platinum-DNA adducts to form and massive apoptosis.Miriplatin appears to be a suitable chemotherapeutic agent for transarterial chemoembolization.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co, Ltd, Osaka, Japan. mitsuharu-hanada@ds-pharma.co.jp

ABSTRACT

Background: Miriplatin (formerly SM-11355), a novel lipophilic platinum complex developed to treat hepatocellular carcinoma, is administered into the hepatic artery using an oily lymphographic agent (Lipiodol Ultra-Fluide) as a carrier. We clarified the usefulness of miriplatin as an agent for transarterial chemoembolization.

Methods: Platinum compounds released from miriplatin into serum, medium and Earle's balanced salt solution were examined. Then, miriplatin and cisplatin were administered to rats bearing hepatoma AH109A tumors in livers. Platinum concentrations in tissues and DNA were assessed.

Results: Miriplatin showed a more sustained release than cisplatin. Dichloro[(1R, 2R)-1, 2-cyclohexane diamine-N, N']platinum, the most abundant platinum compound released from miriplatin, was as effective as cisplatin in inhibiting the growth of cells. Miriplatin was selectively disposed of in tumors, maintained in tumors longer than cisplatin and caused apparent tumor regression inducing platinum-DNA adducts to form and massive apoptosis.

Conclusion: Miriplatin appears to be a suitable chemotherapeutic agent for transarterial chemoembolization.

Show MeSH
Related in: MedlinePlus