Studies on the in vivo disposition of adriamycin in human tumours which exhibit different responses to the drug

Cummings, Jeffrey L.; McArdle, C. S.

doi:10.1038/bjc.1986.141

Cited by 98 publications

(52 citation statements)

References 11 publications

(8 reference statements)

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“…If all the doxorubicin were released from the polymer carrier this could generate doxorubicin levels of 100-300 μM within 100 ml tumour, comparing well with the 0.5-2.0 μM of free doxorubicin found in breast cancer biopsies following treatment with conventional doxorubicin (22). The covalent bond between the doxorubicin and polymer carrier is not broken instantly, however, and the real levels of free, active, drug released are likely to be much lower.…”

Section: Discussionmentioning

confidence: 70%

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Seymour¹

2009

Int J Oncol

258

124

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Abstract. Phase I studies of [N-(2-hydroxypropyl)methacrylamide] (HPMA) copolymer-doxorubicin previously showed signs of activity coupled with 5-fold decreased anthracycline toxicity in chemotherapy-refractory patients. Here we report phase II studies using a similar material (FCE28068) in patients with breast (n=17), non-small cell lung (NSCLC, n=29) and colorectal (n=16) cancer. Up to 8 courses of PK1 (280 mg/m 2 doxorubicin-equivalent) were given i.v., together with 123 Ilabelled imaging analogue. Toxicities were tolerable, with grade 3 neutropenia more prominent in patients with breast cancer (4/17, 23.5% compared with 5/62, 8.1% overall). Of 14 evaluable patients with breast cancer 3 had partial responses (PR), all anthracycline-naïve patients. In 26 evaluable patients with NSCLC, 3 chemotherapy-naïve patients had PR. In contrast, none of the 16 evaluable patients with colorectal cancer responded. Imaging of 16 patients (5 with breast cancer, 6 NSCLC, 5 colorectal cancer) showed obvious tumour accumulation in 2 metastatic breast cancers, although unfortunately no images were obtained from patients who responded. These results show 6/62 PR with limited side effects, supporting the concept that polymer-bound therapeutics can have modified and improved anticancer activities and suggesting the approach should be explored further for breast cancer and NSCLC.

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Section: Discussionmentioning

confidence: 70%

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Seymour¹

2009

Int J Oncol

258

124

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“…Although the exact mechanism by which anthracyclines exert their anticancer activity is still uncertain [5], dominant amongst various mechanisms appear to involve impairment of topoisomerase-IIα activity [6,7], that is consistent with observed DNA intercalation and nuclear localization of the drug [8][9][10]. Biochemical studies show that the drugs inhibit both DNA-directed DNA synthesis [11] and DNA-directed RNA synthesis [12], presumably by their ability to interact with the DNA template primer [13,14].…”

Section: Introductionmentioning

confidence: 97%

“…Biochemical studies show that the drugs inhibit both DNA-directed DNA synthesis [11] and DNA-directed RNA synthesis [12], presumably by their ability to interact with the DNA template primer [13,14]. Owing to aforesaid reasons, research on the interaction of anthracyclines and their analogues with DNA is being actively pursued [1][2][3][4][5][6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Interaction of Calf Thymus DNA with the Ni(II) Complex of Sodium 1,4-Dihydroxy-9,10-Anthraquinone-2-Sulphonate: A Novel Method of Analysis Using Cyclic Voltammetry

Guin

Das

et al. 2012

International Journal of Electrochemistry

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Hydroxy-9,10-anthraquinones are cheaper alternatives to anthracycline drugs. They closely resemble anthracycline drugs both from a structural and functional viewpoint. Electrochemical behavior of the Ni(II) complex (Na 2 [Ni(NaLH) 2 Cl 2 ]·2H 2 O) of sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate (NaLH 2 ), analogue of the core unit of anthracycline anticancer drugs, was studied at physiological pH using cyclic voltammetry. The Ni(II) complex of sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate undergoes diffusion-controlled one-electron reduction that enables performing an electrochemical study on the interaction of the complex with calf thymus DNA. The complex was titrated with increasing concentrations of DNA, and the reduction peak for the unbound complex helped in evaluating binding parameters. Analysis of binding data using nonlinear curve fit in a cyclic voltammetry experiment is the first such attempt. The paper evaluates site size of interaction that also serves as a means to determine stoichiometry of complex formation, between a metal ion and ligand from a DNA interaction study, probably a first of its kind.

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“…There may be a difference between VER-50589 and VER-49009 with respect to metabolism and/or the subsequent disposition of metabolites in HT29 cells as the glucuronides of the two agents are distributed differently between cells and tissue culture medium (Table 2B and C). However, the greater uptake in HCT116 cells of VER-50589 compared with VER-49009 cannot be explained by a difference in metabolism of the two compounds as HCT116 cells do not express uridine diphosphoglucuronosyltransferases (42), and there was no difference in their microsomal metabolism (Table 2D). (Table 1A).…”

Section: X-ray Protein Crystallographymentioning

confidence: 99%

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

Sharp

Prodromou

Boxall

et al. 2007

Molecular Cancer Therapeutics

134

103

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Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K d ) of VER-50589 was 4.5 F 2.2 nmol/L compared with 78.0 F 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC 50 of 21 F 4 nmol/L for VER-50589 compared with 47 F 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI 50 values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 F 15 and 685 F 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and Pglycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI 50 for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as

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Studies on the in vivo disposition of adriamycin in human tumours which exhibit different responses to the drug

Cited by 98 publications

References 11 publications

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

Interaction of Calf Thymus DNA with the Ni(II) Complex of Sodium 1,4-Dihydroxy-9,10-Anthraquinone-2-Sulphonate: A Novel Method of Analysis Using Cyclic Voltammetry

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

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