Macrophage-mediated activation of camptothecin analogue T-2513–carboxymethyl dextran conjugate (T-0128): possible cellular mechanism for antitumor activity

Harada, Mitsunori; Imai, Jun; Okuno, Satoshi; Suzuki, Takehiko

doi:10.1016/s0168-3659(00)00320-5

Cited by 23 publications

(19 citation statements)

References 18 publications

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“…A previous article showed that hG was liberated extracellularly with a high local concentration by neutrophils and macrophages in necrotic tumor areas (40). We used two xenograft models, BALB/c nu/nu nude and NOD/ SCID mice, with or without mature innate immune cells to examine whether the infiltrated innate immune cells in a tumor microenvironment contribute to 9ACG prodrug activation in vivo.…”

Section: Resultsmentioning

confidence: 99%

Antiangiogenesis Targeting Tumor Microenvironment Synergizes Glucuronide Prodrug Antitumor Activity

Ting-Yi

Roffler²,

Hou³

et al. 2009

Clinical Cancer Research

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Purpose: This study is aimed at investigating the in vivo antitumor activity of a novel cellimpermeable glucuronide prodrug, 9-aminocamptothecin glucuronide (9ACG), and elucidating the synergistically antitumor effects of antiangiogenesis therapy by targeting the tumor microenvironment. Experimental Design:We analyzed the antitumor effects of 9ACG alone or combined with antiangiogenic monoclonal antibody DC101on human tumor xenografts by measuring tumor growth and mouse survival in BALB/c nu/nu nude and NOD/SCID mice. The drug delivery, immune response, and angiogenesis status in treated tumors were assessed by high performance liquid chromatography, immunohistochemistry, and immunofluorescence assays. Results: We developed a nontoxic and cell-impermeable glucuronide prodrug, 9ACG, which can only be activated by extracellular h-glucuronidase to become severely toxic. 9ACG possesses potent antitumor activity against human tumor xenografts in BALB/c nu/nu nude mice but not for tumors implanted in NOD/SCID mice deficient in macrophages and neutrophils, suggesting that these cells play an important role in activating 9ACG in the tumor microenvironment. Most importantly, antiangiogenic monoclonal antibody DC101 potentiated single-dose 9ACG antitumor activity and prolonged survival of mice bearing resistant human colon tumor xenografts by providing strong h-glucuronidase activity and prodrug delivery through enhancing inflammatory cell infiltration and normalizing tumor vessels in the tumor microenvironment. We also show that inflammatory cells (neutrophils) were highly infiltrated in advanced human colon cancer tissues compared with normal counterparts. Conclusions: Our study provides in vivo evidence that 9ACG has potential for prodrug monotherapy or in combination with antiangiognesis treatment for tumors with infiltration of macrophage or neutrophil inflammatory cells.

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Section: Resultsmentioning

confidence: 99%

Antiangiogenesis Targeting Tumor Microenvironment Synergizes Glucuronide Prodrug Antitumor Activity

Ting-Yi

Roffler²,

Hou³

et al. 2009

Clinical Cancer Research

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“…The liver, spleen and lymph nodes, however, also showed significant uptake, suggesting recognition by the reticuloendothelial system, which was later investigated and confirmed in studies involving macrophage-mediated activation of T-0128. 289, 290 …”

Section: Macromolecular Architectures For Passive Drug Deliverymentioning

confidence: 99%

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

2010

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This review summarizes the in vivo assessment--preliminary, preclinical, and clinical--of chemotherapeutics derived from camptothecin or a derivative. Camptothecin is a naturally occurring, pentacyclic quinoline alkaloid that possesses high cytotoxic activity in a variety of cell lines. Major limitations of the drug, including poor solubility and inactivity at physiological conditions, prevent full clinical utilization. Camptothecin remains at equilibrium in an active lactone form and inactive hydrolyzed carboxylate form. The active lactone binds to DNA topoisomerase I cleavage complex, believed to be the single site of activity inhibiting DNA religation, resulting in apoptosis. A series of small molecule camptothecin derivatives have been developed that increase solubility, lactone stability and bioavailability to varying levels of success. A number of macromolecular agents have also been described wherein camptothecin(s) are covalently appended or non-covalently associated with the goal of improving solubility and lactone stability, while taking advantage of the tumor physiology to deliver larger doses of drug to the tumor with lower systemic toxicity. With the increasing interest in drug delivery and polymer therapeutics, additional constructs are anticipated. The goal of this review is to summarize the relevant literature for others interested in the field of camptothecin-based therapeutics, specifically in the context of biodistribution, dosing regimens, and pharmacokinetics with the desire of providing a useful source of comparative data. To this end, only constructs where in vivo data is available are reported. The review includes published reports in English through mid-2009.

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“…In presence of the macrophages the free CPT derivative was observed while in the absence of macrophage its content was below the detectability limit. This result further supported that the bioconjugate efficacy lies in the cleavage of the peptide linker and the entry of released drug into tumor cells [126,127].…”

Section: Camptothecinmentioning

confidence: 55%

Polysaccharide-Based Anticancer Prodrugs

Caliceti

Salmaso

Bersani

2009

Macromolecular Anticancer Therapeutics

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So far, polysaccharides have been widely used in pharmaceutical technology as first choice excipients for production of traditional formulations. Nevertheless, in the recent years these natural and semisynthetic macromolecules have been addressed for new challenging applications as functional materials for innovative formulations. Their peculiar physicochemical and biological properties have been exploited to develop macromolecular prodrugs which can exhibit favorable biopharmaceutical properties and enforce the therapeutic performance of the parent drugs. These polymers display, in fact, high biocompatibility and biodegradability, multiple insertion points, and biological properties that can be advantageously exploited in drug delivery. In particular, the multifunctional structures of these polymers are anchoring points for conjugation of several anticancer drugs, which usually suffer from poor physicochemical, biopharmaceutical, and therapeutic properties that limit their therapeutic performance and proper use in anticancer treatment. Polysaccharide-based anticancer prodrugs can be designed to endow derivatives with new bioresponse, targeting, or environmental triggering properties or to combine molecules with synergistic therapeutic effect. Over the years, a variety of synthetic protocols have been set up to conjugate anticancer drugs to the polysaccharide backbone via specific linkages or through spacers which convey to the conjugates selective drug-delivery properties. Furthermore, the intrinsic antitumor activity and cell-targeting properties of few polysaccharides represent an additional value to the final therapeutic systems. Anticancer drugs with different pharmacodynamic, pharmacokinetic, and physicochemical properties have been successfully conjugated to various natural and semisynthetic polysaccharides highlighting the interesting perspectives for exploitation of new promising anticancer polymer therapeutics.

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Macrophage-mediated activation of camptothecin analogue T-2513–carboxymethyl dextran conjugate (T-0128): possible cellular mechanism for antitumor activity

Cited by 23 publications

References 18 publications

Antiangiogenesis Targeting Tumor Microenvironment Synergizes Glucuronide Prodrug Antitumor Activity

Antiangiogenesis Targeting Tumor Microenvironment Synergizes Glucuronide Prodrug Antitumor Activity

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

Polysaccharide-Based Anticancer Prodrugs

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