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. 2009 Jan;100(1):189-94.
doi: 10.1111/j.1349-7006.2008.01010.x. Epub 2008 Nov 24.

Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of human hepatoma cells orthotopically implanted in nude rats

Affiliations

Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of human hepatoma cells orthotopically implanted in nude rats

Mitsuharu Hanada et al. Cancer Sci. 2009 Jan.

Abstract

Miriplatin is a lipophilic platinum complex which contains myristates as leaving groups and diaminocyclohexane as a carrier ligand. In order to examine in vivo the antitumor activities of miriplatin suspended in an oily lymphographic agent (Lipiodol Ultra-Fluide, LPD) against human hepatocellular carcinoma (HCC) after the intra-hepatic arterial administration, we have developed a novel orthotopic model of HCC in which the human hepatoma cell line Li-7 was successively implanted and maintained in the liver of nude rats. Li-7 tumors established in nude rat livers displayed a trabecular structure similar to their original morphology, and were exclusively supplied by the hepatic artery, suggesting that they exhibited in part the conditions of human HCC. Miriplatin suspended in LPD (miriplatin/LPD) administered into the hepatic artery of this model dose-dependently inhibited the growth of Li-7 tumors without markedly enhancing body weight loss and caused a significant reduction in the growth rate at a dose of 400 microg/head compared to LPD alone. In addition, at the therapeutic dose, miriplatin/LPD as well as cisplatin suspended in LPD (400 microg/head) was shown to be more active than zinostatin stimalamer suspended in LPD (20 microg/head) against Li-7 tumors after a single intra-hepatic arterial administration. These results suggest miriplatin to be a suitable candidate for use in transarterial chemoembolization.

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Figures

Figure 1
Figure 1
Formation of platinum‐DNA adducts and induction of apoptosis in Li‐7 cells after treatment with miriplatin/LPD (oily lymphographic agent [Lipiodol Ultra‐Fluide®]) and cisplatin/LPD for 3 days. One day after the plating of Li‐7 cells into microplates, cells were treated for 3 days with the indicated concentrations of miriplatin/LPD and cisplatin/LPD added into Falcon cell culture inserts. (Upper) Formation of platinum‐DNA adducts. The amounts of platinum in DNA isolated from cells were quantitatively analyzed at 265.9 nm by flameless atomic absorption spectrometry. NT; not tested, ND; not detected. (Lower) Induction of apoptosis. The population of sub‐G1 cells was determined by flow cytometry after propidium iodide staining. All data are shown as the mean ± SD of triplicates.
Figure 2
Figure 2
Histology of Li‐7 tumors implanted in nude rat livers. Resected liver was fixed in formalin, and sections were stained with hematoxylin and eosin. ×100.
Figure 3
Figure 3
Blood supply to Li‐7 tumors established in nude rat livers. A 100% (w/v) barium sulfate suspension was injected into the hepatic artery (left) or the portal vein (right) at a dose of 0.5 mL/head or 5.0 mL/head, respectively. Immediately after the administration, livers were resected, fixed in formalin, and radiographed with a soft X‐ray machine. Yellow circles indicate tumor sites.
Figure 4
Figure 4
Dose‐dependent antitumor activities of miriplatin/LPD (oily lymphographic agent [Lipiodol Ultra‐Fluide®]) after intra‐hepatic arterial administration. Miriplatin/LPD and LPD alone were injected into the hepatic artery of Li‐7 tumor‐bearing nude rats at the volume of 0.02 mL/head. Fourteen days later, the tumor growth rates and changes in body weight were evaluated. All results are given as the mean ± SD (n = 7). A Dunnett test of the tumor growth rate or change in body weight at day 14 demonstrated a significant difference, *P < 0.01, comparing the group treated with LPD alone to those treated with miriplatin/LPD.
Figure 5
Figure 5
Antitumor activities of miriplatin, cisplatin, and zinostatin stimalamer suspended in LPD (oily lymphographic agent [Lipiodol Ultra‐Fluide®]) at the therapeutic dose. Each agent suspended in LPD and LPD alone were injected into the hepatic artery of Li‐7 tumor‐bearing rats at the volume of 0.02 mL/head. Fourteen days later, the tumor growth rates and changes in body weight were evaluated. No agent was administered in the untreated group (only measurement of tumor size) or sham‐operated group (measurement of tumor size and occlusion of the gastroduodenal artery). All results are given as the mean ± SD (n = 7). A Dunnett test of the tumor growth rate or change in body weight at day 14 demonstrated a significant difference, **P < 0.05, comparing the group treated with LPD alone to those treated with agents at the therapeutic dose (colored), *P < 0.05, comparing the group treated with LPD alone to that treated with zinostatin stimalamer/LPD (100 µg/head).

References

    1. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362: 1907–17. - PubMed
    1. Bruix J, Sherman M, Llovet JM et al . Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona‐2000 EASL conference. J Hepatol 2001; 35: 421–30. - PubMed
    1. Llovet JM, Beaugrand M. Hepatocellular carcinoma. J Hepatol 2003; 38: S136–49. - PubMed
    1. Lo CM, Nygan H, Tso WK et al . Randomized controlled trial of transarterial Lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatol 2002; 35: 1164–71. - PubMed
    1. Llovet JM, Real MI, Montaña X et al . Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet 2002; 359: 1734–9. - PubMed