Intra-Arterial Hepatic Chemotherapy with Pirarubicin

Rougier, P; Munck, Jean‐Nicolas; Élias, Dominique; Hérait, Patrice; Bognel, C; Gosse, C; Lasser, P

doi:10.1097/00000421-199012001-00002

Cited by 19 publications

(9 citation statements)

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“…For this difficult to treat tumor, the results of the present study provide an encouraging prospect for its control. The dose used (100 mg ⁄ kg free pirarubicin equivalent, more than 10 times higher dose than free drug) was well tolerated without detectable toxicity (29) in this model. Further studies investigating the use of higher doses, or multiple weekly ⁄ monthly cycles are warranted for more complete eradiation of metastatic foci.…”

Section: Resultsmentioning

confidence: 90%

“…(22)(23)(24)(25)(26) It exhibits faster intracellular uptake and more potent antitumor activity than doxorubicin in vivo due to its pyranyl group and lipophilic properties. (26)(27)(28)(29)(30)(31) However, it exerts poor tumor targeting properties as is common to other low molecular weight anticancer agents. (26)(27)(28)(29)(30)(31)(32) The rationale for the choice of pirarubicin for the SMA-micelle is that once SMA-pirarubicin micelles reach the target tumor tissue, the micelles will release free pirarubicin slowly in a sustained manner in the vicinity of tumor cells by virtue of the EPR effect.…”

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confidence: 99%

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In vitro and in vivo evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases

et al. 2010

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Pirarubicin is a derivative of doxorubicin with improved intracellular uptake and reduced cardiotoxicity. We have prepared a micellar formulation of pirarubicin using styrene-maleic acid copolymer (SMA) of mean molecular weight of 1.2 kDa, which exhibits a mean diameter of 248 nm in solution. Being a macromolecule, SMA-pirarubicin micelles exhibit excellent tumor targeting capacity due to the enhanced permeability and retention (EPR) effect.Here we report the antitumor activity of SMA-pirarubicin micelles on human colon and breast cancer cell lines in vitro, and a murine liver metastasis model in vivo. Metastatic tumor microvasculature, necrosis, apoptosis, proliferation, and survival were also investigated using immunohistochemistry for Ki-67, active caspase-3, and CD34, respectively. Drug cytotoxicity in vitro was assessed using MTT (3-[4,5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide) assay. In vivo, SMA-pirarubicin was administered at 100, 150, or 200 mg/kg (pirarubicin equivalent). Tumor microvasculature was also assessed using scanning electron microscopy. Styrene-maleic acid copolymer (SMA)-pirarubicin micelles were toxic against human colorectal and breast cancer cells in vitro. IC 50 was at or below 1 lM, free pirarubicin equivalent. In vivo, SMA-pirarubicin at 100 mg/kg reduced tumor volume by 80% and achieved a survival rate of 93% at 40 days after tumor inoculation. Styrenemaleic acid copolymer (SMA)-pirarubicin micelles demonstrated potent antitumor activity in this liver metastases model, contributing to prolonged survival. Histological examination of tumor nodules showed significant reduction and proliferation of tumor cells (>90%). The present results suggest that investigation of the effect of multiple dosing at later time points to further improve survival is warranted. (Cancer Sci 2010; 101: 1866-1874 T he standard treatment for colorectal cancer is surgical removal. However, 50-70% of these patients will develop metastasis to the liver, often with multiple tumor nodules spread throughout the different lobes that limit the control of metastatic tumors either by surgery or radiation. Thus, chemotherapy for colorectal liver metastases has an important role as either adjuvant or neoadjuvant therapy to surgery as well as palliation for unresectable disease.In conventional chemotherapy, drugs used clinically are low molecular weight (MW) compounds generally about 500-1000 Da. This means that they diffuse systemically resulting in indiscriminate drug exposure to both tumor and normal tissues. On the contrary, macromolecular drug delivery (>40 kDa) confers more selective tumor delivery, and thus reduced toxicity in normal organs.(1,2) This tumor-preferred macromolecular drug delivery is now considered as the EPR (enhanced permeability and retention) effect.(1-3) The EPR effect reflects the unique vascular properties in tumor tissues. The EPR effect consists of two aspects. One is anatomical and physiological abnormality; tumor blood vessels lack pericytes (smooth muscle layer) and are s...

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Section: Resultsmentioning

confidence: 90%

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confidence: 99%

In vitro and in vivo evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases

et al. 2010

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“…[1][2][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.…”

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confidence: 99%

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

Kishimoto

Miyazawa

Fukushima

et al. 2000

Japanese Journal of Cancer Research

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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...

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“…It is necessary to find better drugs, designed for this mode of delivery, such as THP Adriamycin, which has better phamacological than doxorubicin and penetrates the tumor cells better when administered intra-arterially [17]. Lipiodol may ameliorate the therapeutic results [15,18], but new occlusive agents, such as microcapsules Or liposomes~ be tested to…”

Section: Third Studymentioning

confidence: 99%

Efficacy of chemoembolization for hepatocellular carcinomas: Experience from the gustave roussy institute and the bicetre hospital

et al. 1993

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Chemoembolization (CE) has been used for more than 10 years to treat hepatocellular carcinoma (HCC) in our departments, and three studies have been done. The first was a retrospective study on 232 patients in which CE was performed with doxorubicin and Gelfoam with or without Lipiodol; the response rate was 41% (34.7-47.3%) and survival was better for Okuda stage I disease than for stages I1 and 111 (2-year survival 82, 29, and 0% respectively); for patients with Lipiodol retention the response rate was over 50%. The second study compared CE with doxorubicin and Gelfoam to symptomatic treatment in a randomized manner; it included 42 patients and failed to demonstrate a survival advantage ( 1 -year survival: CE 24% vs. control 31%; NS). The third study is ongoing and tests CE with cis-platinum, Lipiodol, and Gelfoam.According to our experience prospective randomized studies are warranted to define clearly the best indications for CE in HCC.

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Intra-Arterial Hepatic Chemotherapy with Pirarubicin

Cited by 19 publications

References 0 publications

In vitro and in vivo evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases

In vitro and in vivo evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases

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

Efficacy of chemoembolization for hepatocellular carcinomas: Experience from the gustave roussy institute and the bicetre hospital

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