Campthotecin Design and Delivery Approaches for Elevating Anti‐Topoisomerase I Activities <i>in Vivo</i>

Burke, Thomas G.; Bom, David

doi:10.1111/j.1749-6632.2000.tb07023.x

Cited by 36 publications

(18 citation statements)

References 28 publications

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“…Drug carrier formulations of camptothecins have been aggressively pursued in part because the formulations improve the availability of the active lactone form of the drug (30). The liposomal formulation of irinotecan developed by our group (Irinophore C) maintains the drug in its active form within the liposome, extends its plasma half-life, and improves accumulation of drug in the tumor (16).…”

Section: Discussionmentioning

confidence: 99%

Irinophore C, a Novel Nanoformulation of Irinotecan, Alters Tumor Vascular Function and Enhances the Distribution of 5-Fluorouracil and Doxorubicin

Baker

Lam

Kyle

et al. 2008

Clinical Cancer Research

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Purpose: To examine the antitumor effects of Irinophore C, a nanopharmaceutical formulation of irinotecan, on the tissue morphology and function of tumor vasculature in HT-29 human colorectal tumors. Experimental Design: Fluorescence microscopy was used to map and quantify changes in tissue density, tumor vasculature, hypoxia, and the distribution of Hoechst 33342, a perfusion marker, and the anticancer drug, doxorubicin. Noninvasive magnetic resonance imaging was used to quantify K trans , the volume transfer constant of a solute between the blood vessels and extracellular tissue compartment of the tumor, as a measure of vascular function. Following treatment with Irinophore C, 19F magnetic resonance spectroscopy was used to monitor the delivery of 5-fluorouracil (5-FU) to the tumor tissue, whereas scintigraphy was used to quantify the presence of bound [ ), and 5-FU (P = 0.0002) in the tumor. Vascular endothelial growth factor and interleukin-8, two proangiogenic factors, were down-regulated, whereas the antiangiogenic factorTIMP-1was up-regulated in Irinophore C-treated tumors. Conclusions: Irinophore C treatment improves the vascular function of the tumor, thereby reducing tumor hypoxia and increasing the delivery and accumulation of a second drug. Reducing hypoxia would enhance radiotherapy, whereas improving delivery of a second drug to the tumor should result in higher cell kill.The clinical management of metastatic disease originating from colon/colorectal cancer remains challenging. The liver is the most common site of distant metastases for colorectal cancer, with 70% of patients presenting with liver metastases followed by the lungs, bone, and brain (1, 2). At present, the only cure is complete surgical removal of the primary tumor if diagnosed early; however, up to 45% of these patients still relapse with metastatic disease. Standard of care for first-line therapy in patients is a combination of 5-fluorouracil (5-FU; plus leucovorin) with either irinotecan (FOLFIRI) or oxaliplatin (FOLFOX; ref.3). The treatments are associated with prolonged median survivals of 18 to 21 months. Capecitabine, an oral fluoropyrimidine carbamate, has also been used in combination with 5-FU, and clinical data suggest that this combination is comparable with the FOLFIRI and FOLFOX regimens (4, 5). In practice, however, combination therapy with capecitabine is limited because of severe toxicities such as hand-foot syndrome, diarrhea, nausea, vomiting, and bone marrow suppression (4, 5). More recently, monoclonal antibodies targeting the epidermal growth factor receptor, such as cetuximab and panitumumab, have been used in combination with standard chemotherapy with promising results (6). The safety and efficacy of bevacizumab, the monoclonal antibody that targets vascular endothelial growth factor (VEGF; ref. 7), in combination with FOLFIRI or FOLFOX, was also evaluated recently (8,9). Although both studies were carried out with small Cancer Therapy: Preclinical

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Section: Discussionmentioning

confidence: 99%

Irinophore C, a Novel Nanoformulation of Irinotecan, Alters Tumor Vascular Function and Enhances the Distribution of 5-Fluorouracil and Doxorubicin

Baker

Lam

Kyle

et al. 2008

Clinical Cancer Research

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“…The first includes the introduction of a side chain on the indolizinoquinoline moiety. For example, the 9-dimethylaminomethyl group of topotecan decreases the protein binding of the carboxylate to human serum albumin (Burke et al, , 2000, thus increasing the concentration of the active lactone form. The second includes modification of the lactone E-ring to decrease its rate of hydrolysis.…”

mentioning

confidence: 99%

Novel Stable Camptothecin Derivatives Replacing the E-Ring Lactone by a Ketone Function Are Potent Inhibitors of Topoisomerase I and Promising Antitumor Drugs

et al. 2007

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The E-ring lactone is the Achilles' heel of camptothecin derivatives: although it is considered necessary for the inhibition of the enzyme topoisomerase I (topo1), the opening of the lactone into a carboxylate abolishes the generation of topo1-mediated DNA breaks. S38809 is a novel camptothecin analog with a stable 5-membered E-ring ketone; therefore, it lacks the lactone function. DNA relaxation and cleavage assays revealed that S38809 functions as a typical topo1 poison by stimulating DNA cleavage at T2G sites. The activity was strongly dependent on the stereochemistry of the C-7 carbon atom that bears the hydroxy group. S38809 proved to be a potent cytotoxic agent, with a mean IC 50 of 5.4 nM versus 11.6 nM for topotecan and 3.3 nM for SN38 (the active metabolite of irinotecan) on a panel of 31 human tumor cell lines. The cytotoxicity of S38809 and its ability to stabilize cleavable complexes was considerably reduced in camptothecin-resistant cells that express a mutated topo1, confirming that topo1 is its primary target. Cell death induced by topo1 poisoning requires the conversion of DNA single-strand breaks into double-strand breaks that can be detected by the formation of phosphorylated histone H2AX. In HCT116 cells, topotecan, SN38, and S38809 induced histone H2AX phosphorylation in S phase of the cell cycle, with S38809 being as potent as SN38 and 5-fold more potent than topotecan. In vivo, S38809 showed a marked antitumor activity against HCT116 xenografts. These findings open a new route for improving the pharmacological properties of camptothecin derivatives.

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“…However, the open ring form of CPT is inactive and must be closed to inhibit topoisomerase I. Besides, the CPT molecule is highly susceptible to hydrolysis and poorly soluble in water, a finding which restricts the clinical application of CPTs (25,26). It should be mentioned that solubility increases as the environment becomes more acidic, as it exists in many cancer cells' microenvironment (27).…”

Section: Camptothecins: From Thermodynamics To Applicationmentioning

confidence: 99%

From Drug Delivery Systems to Drug Release, Dissolution, IVIVC, BCS, BDDCS, Bioequivalence and Biowaivers

Karalis

Magklara²,

Shah³

et al. 2010

Pharm Res

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This is a summary report of the conference on drug absorption and bioequivalence issues held in Titania Hotel in Athens (Greece) from the 28(th) to the 30(th) of May 2009. The conference included presentations which were mainly divided into three sections. The first section focused on modern drug delivery systems such as polymer nanotechnology, cell immobilization techniques to deliver drugs into the brain, nanosized liposomes used in drug eluting stents, encapsulation of drug implants in biocompatible polymers, and application of differential scanning calorimetry as a tool to study liposomal stability. The importance of drug release and dissolution were also discussed by placing special emphasis on camptothecins and oral prolonged release formulations. The complexity of the luminal environment and the value of dissolution in lyophilized products were also highlighted. The second session of the conference included presentations on the Biopharmaceutics Classification Scheme (BCS), the Biopharmaceutics Drug Disposition Classification System (BDDCS), and the role of transporters in the classification of drugs. The current status of biowaivers and a modern view on non-linear in vitro-in vivo (IVIVC) correlations were also addressed. Finally, this section ended with a special topic on biorelevant dissolution media and methods. The third day of the conference was dedicated to bioequivalence. Emphasis was placed on high within-subject variability and its impact on study design. Two unresolved issues of bioequivalence were also discussed: the use of generic antiepileptic drugs and the role of metabolites in bioequivalence assessment. Finally, the conference closed with a presentation of the current regulatory status of WHO and EMEA.

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Campthotecin Design and Delivery Approaches for Elevating Anti‐Topoisomerase I Activities in Vivo

Cited by 36 publications

References 28 publications

Irinophore C, a Novel Nanoformulation of Irinotecan, Alters Tumor Vascular Function and Enhances the Distribution of 5-Fluorouracil and Doxorubicin

Irinophore C, a Novel Nanoformulation of Irinotecan, Alters Tumor Vascular Function and Enhances the Distribution of 5-Fluorouracil and Doxorubicin

Novel Stable Camptothecin Derivatives Replacing the E-Ring Lactone by a Ketone Function Are Potent Inhibitors of Topoisomerase I and Promising Antitumor Drugs

From Drug Delivery Systems to Drug Release, Dissolution, IVIVC, BCS, BDDCS, Bioequivalence and Biowaivers

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