Synthesis of new camptothecin analogs with improved antitumor activities

Niizuma, Satoshi; Tsukazaki, Masao; Suda, Hitomi; Murata, Takeshi; Ohwada, Jun; Ozawa, Sawako; Fukuda, Hiroshi; Murasaki, Chikako; Kohchi, Masami; Morikami, Kenji; Yoshinari, Kiyoshi; Endo, Mika; Ura, Masako; Tanimura, Hiromi; Miyazaki, Yoko; Takasuka, Tsuyoshi; Kawashima, Akira; Nanba, Eitaro; Nakano, Kounosuke; Ogawa, Kotaro; Kobayashi, Kazuo; Okabe, Hisafumi; Umeda, Isao; Shimma, Nobuo

doi:10.1016/j.bmcl.2009.02.031

Cited by 15 publications

(16 citation statements)

References 8 publications

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“…While previous studies have already characterized the IC 50 of SN-38 for HCT116 cells in 2D cultures, these values range three orders of magnitude (50 - 0.5 nM) making comparisons with literature values difficult. 34,51 The IC 50 value for the HCT116 cells in the paper scaffolds (0.014 ± 0.006 μM) was much higher than for monolayer cultures (0.005 ± 0.001 μM). These data are summarized in Figure S5.…”

Section: Resultsmentioning

confidence: 93%

Assessing chemotherapeutic effectiveness using a paper-based tumor model

Boyce

LaBonia

Hummon

et al. 2017

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In vitro models for screening new cancer chemotherapeutics often rely on two-dimensional cultures to predict therapeutic potential. Unfortunately, the predictive power of these models is limited, as they fail to recapitulate the complex three-dimensional environments in tumors that promote the development of a chemoresistant phenotype. In this study, we describe the preparation and characterization of paper-based cultures (PBC) engineered to assess chemotherapeutic effectiveness in three dimensional, diffusion-limited environments. Similar environments are found within poorly vascularized tumors. These cultures, which are assembled by stacking together cell-laden paper scaffolds to yield thick tissue-like structures, generate monotonic gradients vertically through the culture and provide distinct chemical environments for each scaffold. After prolonged incubation, the scaffolds can simply be peeled apart and analyzed to relate cellular responses to the chemical environment experienced at that scaffold. Through fluorescence imaging, viable and proliferative cell populations were mapped within a stacked culture and found to be most abundant in scaffolds close to the nutrient-rich medium. By adjusting the cell density, we modulated the spatiotemporal evolution of oxygen gradients across the cultures and correlated these environmental changes with cellular sensitivity to SN-38 exposure. From these results, we showed that differences in the oxygen gradients produced cellular populations with significantly different chemosensitivities. Through this work, we highlight PBCs ability to serve as an analytical model capable of determining chemotherapeutic effectiveness under a range of chemical environments.

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Section: Resultsmentioning

confidence: 93%

Assessing chemotherapeutic effectiveness using a paper-based tumor model

Boyce

LaBonia

Hummon

et al. 2017

Analyst

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“…In man, TP300 is converted non-enzymatically to TP3076, then metabolized to TP3011 by aldehyde oxidase 1 (AOX1; Figure 1) [9]. TP3011 and TP3076 are equipotent as Topo-1 inhibitors, with IC 50 in the sub-nanomolar range HCT-116 colorectal cancer cells in vitro [10]. Importantly, TP3076 lacks a phenolic-OH group in its structure such that it cannot be glucuronidated in the same way as irinotecan and also should not be influenced to any great extent by polymorphisms in the UGT1A1 gene.…”

Section: Introductionmentioning

confidence: 99%

Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses

et al. 2012

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BackgroundA Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011.MethodsEligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs).Results32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m2. MTD was 10 mg/m2; DLTs at 12 (2/4 patients) and 10 mg/m2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhoea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and Cmax from 1–10 mg/m2. Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion.ConclusionsTP300 had predictable hematologic toxicity, and diarrhoea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage.Trial registrationEU-CTR2006-001345-33

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“…BCRP is a half ATP-binding cassette (ABC) efflux transporter that is associated with resistance to camptothecin agents [5,6]. The inhibitor 3076 is not a substrate of BCRP and the antitumor activity of 3076 is higher than that of SN-38 [1,7], regardless of the level of BCRP expression. No acute diarrhea, which results from acetylcholinesterase inhibition, has been observed during treatment with TP300 [7].…”

Section: Introductionmentioning

confidence: 99%

“…Although 3011 is not as potent as 3076, it also has antiproliferative activity [1]. It has been reported that predicting the intrinsic clearance of drugs metabolized by aldehyde oxidase from in vitro-in vivo correlations is challenging [8].…”

Section: Introductionmentioning

confidence: 99%