Effect of arterial administration of high-molecular-weight anticancer agent SMANCS with lipid lymphographic agent on hepatoma: a preliminary report

Konno, Toshimitsu; Maeda, Hiroshi; Iwai, Ken; Tashiro, Seiki; Maki, Shôjirô; Morinaga, Tetsuo; Mochinaga, Mizuho; Hiraoka, Takehisa; Yokoyama, Ikuzo

doi:10.1016/0277-5379(83)90028-7

Cited by 315 publications

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“…(1,3,(6)(7)(8)(9)(10)(11)(12) We have previously characterized tumor vessels as dilated and tortuous with irregular diameters and aberrant branching as well as leakage of polymeric resin (6)(7)(8)(9) and loose endothelial cell-cell gap junctions as large as 600-800 nm. (3,10,11) In addition, we and others identified excessive production of mediators of vascular permeability including bradykinin, nitric oxide, prostaglandins, and vascular endothelial growth factor (VEGF) that also contribute to hyperpermeability of tumor vessels as well as host vessels at the periphery of tumors.(12-16) These differences were first reported by Maeda et al( [1][2][3][16][17][18][19][20] Tumor-associated lymphatic vessels also show irregularities in structure and some tumors show a complete lack of lymphatics, and therefore drainage has been found to be impaired in tumors.In addition to tumor targeting, macromolecular drugs are known to have increased plasma circulation times; the half-life in circulation and intratumoral concentrations can be as high as 20-to 200-fold (2,9,(17)(18)(19)(20)(21) compared to low MW free drugs. In the clinical setting, tumor-selective targeting using macromolecules has been observed with gallium scintigraphy, where radioactive gallium binds to tumor-associated transferrin (90 kDa), and SMANCS (polystyrene-co-maleic acid conjugated neocarzinostatin) ⁄ Lipiodol, with the high electron density of lipiodol, both exclusively accumulate in tumors.…”

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“…( [1][2][3][16][17][18][19][20] Tumor-associated lymphatic vessels also show irregularities in structure and some tumors show a complete lack of lymphatics, and therefore drainage has been found to be impaired in tumors.…”

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confidence: 99%

“…In the clinical setting, tumor-selective targeting using macromolecules has been observed with gallium scintigraphy, where radioactive gallium binds to tumor-associated transferrin (90 kDa), and SMANCS (polystyrene-co-maleic acid conjugated neocarzinostatin) ⁄ Lipiodol, with the high electron density of lipiodol, both exclusively accumulate in tumors. (2,(17)(18)(19)(20)(21) Pirarubicin is a pyranyl derivative of doxorubicin with a mode of action involving generation of reactive oxygen species. (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.…”

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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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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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“…HAI of SMANCS administered as a formulation with the lipid contrast medium Lipiodol is associated with a tumoursystemic drug concentration ratio of greater than 2,500. In a pilot phase II study (Konno et al, 1983), 44 patients with advanced hepatoma received a total of 88 bolus injections of SMANCS/Lipiodol via the hepatic artery. Treatment resulted in a decrease in alpha-fetoprotein in 86% of patients and a reduction in tumour size in 95% of patients.…”

Section: Pharmacological Rationale For Regional Chemotherapymentioning

confidence: 99%

Hepatic arterial chemotherapy for metastatic colorectal carcinoma

Takats

Kerr²,

Poole³

et al. 1994

Br J Cancer

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Summary In this review, the rationale of regional chemotherapy for treatment of hepatic metastases in advanced colorectal carcinoma is discussed. Pharmacokinetic principles and early clinical experience of hepatic arterial drug administration are summarised. The regional advantage of fluoropyrimidine compounds in this setting is well established, and recent evidence suggests that 5-fluorouracil (5-FU) is more efficacious than the analogue 5-fluoro-2'-deoxyuridine (FUDR). However, while significantly higher clinical response rates can be achieved with hepatic arterial infusion (HAI) chemotherapy compared with conventional intravenous drug administration, patient survival benefit is not significantly different. Several novel approaches to overcome the limitations of HAI therapy are currently being explored. These include concomitant use of biodegradable microspheres, which both slow tumour blood flow and enhance tumour drug uptake, and use of vasoactive agents to redistribute arterial blood flow towards tumours. In addition, novel chemotherapeutic agents which exploit unique biological characteristics of hepatic tumours are entering clinical trial.The conventional notion of chemotherapy is of a truly systemic treatment designed to combat widely disseminated malignant disease. Colorectal carcinoma is relatively unresponsive to chemotherapy (Mayer, 1992), despite an increasing understanding of drug mechanisms of action at the molecular level. To date, systemic 5-FU plus folinic acid is considered the optimum treatment for metastatic colorectal cancer, yielding response rates of around 25% and median survival of around 12 months (Piedbois et al., 1992). These disappointing results reflect, in part, the narrow therapeutic ratio of 5-FU and the presence of associated severe systemic side-effects limiting dose escalation. Regional chemotherapy affords an alternative method of cytotoxic drug administration which circumvents the constraints of systemic administration, while introducing the concept of targeted drug delivery to metastatic disease localised to specific components of the body.Three levels of tumour targeting have been described (Widder et al., 1979): (1) selective drug delivery to the tumourbearing organ, (2) drug delivery biased to tumour rather than to normal tissue within that organ and (3) enhancement of uptake of cytotoxic drug by malignant cells. In this context, regional chemotherapy constitutes first-order targeting. Currently, the value of this method of drug delivery is being assessed in a number of different malignancies, but experience is greatest in the treatment of hepatic metastases from colorectal carcinoma.Colorectal carcinoma is the second most common malignancy in the UK and the cause of over 19,000 deaths per year. Epidemiological studies show that the incidence of colorectal carcinoma is increasing, with approximately 28,000 new cases now being diagnosed annually. Up to 50% of patients with colorectal carcinoma develop liver metastases, from which as many as 70% of patients will subsequen...

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“…In the case of unresectable tumour, regional intra-arterial treatment has become the treatment of choice, leading to response rates of 55 to 90% (Onohara et al, 1988;Sasaki et al, 1997;Fujimoto et al, 1985;Konno et al, 1983;Beppu et al, 1991). However, for patients with extrahepatic disease, systemic treatment might be the only therapeutical option.…”

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Pilot study with pegylated liposomal doxorubicin for advanced or unresectable hepatocellular carcinoma

et al. 2001

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Effect of arterial administration of high-molecular-weight anticancer agent SMANCS with lipid lymphographic agent on hepatoma: a preliminary report

Cited by 315 publications

References 4 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

Hepatic arterial chemotherapy for metastatic colorectal carcinoma

Pilot study with pegylated liposomal doxorubicin for advanced or unresectable hepatocellular carcinoma

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