Antitumor activity of CKD-602, a camptothecin derivative, in a mouse glioma model

Kim, Chae Yong; Lee, Su Jung; Kim, Seung Ki; Park, Shin Young; Wang, Kyu Chang; Cho, Byung Kyu

doi:10.1016/j.jocn.2011.03.032

Cited by 3 publications

(13 citation statements)

References 27 publications

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“…The combination protocol with cilengitide plus belotecan can help to reduce the dose of belotecan, which has several DLTs. In this experiment, we used a half‐dose of belotecan for in vivo treatment, compared to the previous in vivo study with belotecan monotherapy . The treatment regimen of a half‐dose reduction of belotecan plus cilengitide was no less effective than a full‐dose of belotecan monotherapy, as in our previous study .…”

Section: Discussionmentioning

confidence: 89%

“…With better aqueous solubility and bioavailability, belotecan, a camptothecin analog, has shown potent anticancer activity against various tumor cells in vitro and in vivo . Moreover, we previously demonstrated that belotecan‐induced apoptotic cell death in glioblastoma cells both in vitro and in vivo . Recently, a multicenter phase II clinical trial by Lee et al .…”

Section: Discussionmentioning

confidence: 97%

“…Belotecan showed greater antitumor activity while exhibiting a reduced toxicity profile compared to irinotecan or topotecan in recent clinical trials . In previous studies, we demonstrated, both in vitro and in vivo , that belotecan had anticancer effects on human glioblastoma cell lines …”

mentioning

confidence: 84%

“…Cilengitide was administered intraperitoneally at a dose of 20 mg/kg daily and the belotecan at a dose of 10 mg/kg every 4 days. Based on previous in vivo studies, the optimal dose was calculated . The control group of animals was injected with saline only.…”

Section: Methodsmentioning

confidence: 99%

“…Belotecan (CKD‐602), 7‐[2‐( N ‐isopropylamino)ethyl]‐(20S)‐camptothecin, is a new water‐soluble synthetic analog of camptothecin . Belotecan showed greater antitumor activity while exhibiting a reduced toxicity profile compared to irinotecan or topotecan in recent clinical trials .…”

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confidence: 99%

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Combination therapy of cilengitide with belotecan against experimental glioblastoma

Kim

Lee

Kim

et al. 2013

Intl Journal of Cancer

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The prognosis of patients diagnosed with glioblastoma remains dismal in spite of the current concomitant chemoradiotherapy with temozolomide. In particular, the resistance to temozolomide appears to be the greatest obstacle to the treatment of glioblastoma. In the present study, we evaluated in vitro and in vivo the antitumor effects of combination therapy of cilengitide with belotecan, a camptothecin derivate, to treat experimental glioblastoma. The therapeutic effects of the drugs on the U87MG and U251MG human glioblastoma cell lines were assessed using in vitro cell viability and apoptosis assays. The combination treatment group with cilengitide and belotecan enhanced the cytotoxic effects to the glioblastoma cell lines and increased the apoptosis of the tumor cells compared to monotherapy with either drug alone in vitro. Nude mice with established U87MG glioblastoma were assigned to the following four groups: control, cilengitide, belotecan and combination treatment. The volume of tumors and length of survival were also measured. Animals in the combination therapy group demonstrated a significant reduction of tumor volume and an increase in survival (p < 0.05). Immunohistochemistry revealed a decrease in angiogenesis by cilengitide and an increase in apoptosis by cilengitide and belotecan in vivo. The combination therapy of cilengitide with belotecan presented more cytotoxic effects compared to the monotherapy of either drug in vitro and in vivo. This combination protocol may serve as an alternative treatment option for glioblastoma.Glioblastoma is the most common malignant tumor of the central nervous system. 1 Currently, microsurgery and adjuvant concomitant chemoradiotherapy with temozolomide are the recommended first-line treatment for patients with primary glioblastoma.2 Despite recent advances in the treatment of glioblastoma, the prognosis for patients with newly diagnosed glioblastoma remains dismal; hence, these patients survive for no more than 2 years after diagnosis. Currently, there are no proven effective therapeutic options against temozolomide resistance. Therefore, there is a great interest in finding novel therapeutic agents for overcoming the resistance to temozolomide.Cilengitide (EMD121974), a cyclic Arg-Gly-Asp (RGD)-based peptide, is an antagonist of integrins avb3 and avb5 and has been thought to primarily exert an antiangiogenic effect on malignant glioma cells.3 Moreover, cilengitide may also have a direct effect on attachment, migration, invasion and viability of tumor cells. 4 Recently, cilengitide has become of great interest as a novel therapeutic agent for primary and recurrent glioblastoma. [4][5][6][7] Preliminary reports suggested that cilengitide exhibited a preferential benefit over the current concomitant chemoradiotherapy with temozolomide in patients with O 6 -methyl-guanine DNA methyltransferase (MGMT) promoter methylation. 8 Belotecan showed greater antitumor activity while exhibiting a reduced toxicity profile compared to irinotecan or topotecan in recent clinical tr...

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Combination therapy of cilengitide with belotecan against experimental glioblastoma

Kim

Lee

Kim

et al. 2013

Intl Journal of Cancer

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Current status of CPT and its analogues in the treatment of malignancies

Zekria

Cai

et al. 2015

Phytochem Rev

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Synthesis, Biological Evaluation, and in Vivo Imaging of the first Camptothecin–Fluorescein Conjugate

et al. 2013

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The first synthesis and photophysical properties of a fluorecently labeled camptothecin derivative, namely, camptothecin-FI (CPT-FI), an antitumoral agent that targets topoisomerase I, are reported. The preparation of this fluorescent conjugate is based on a highly convergent and flexible approach which enables the rapid chemical modification of the AB ring system of this fragile pentacyclic alkaloid, aimed at introducing an anchoring point to graft the fluorophore. The selection of a fluorescein analogue as the reporter group has enabled us to get the first green-emitting CPT conjugate exhibiting valuable spectral properties and retaining biological properties of native CPT. Indeed, in biological models, i.e., glioma cell lines U87 and/or T98, the kinetics of cell endocytosis, as well as the efficacy of CPT-FI were compared to those of CPT. CPT-FI fluorescence was measured in the cytosolic compartment of T98 glioma cells from 5 min treatment and remained detectable until 48 h. As CPT, CPT-FI drastically inhibited glioma growth and cell cycle but exhibited a reduced affinity as compared to the native CPT. In vivo and ex vivo imaging studies of CPT-FI intratumoraly injected into a model of NIH-3T3 murine tumor xenografts in nude mice, showed accumulation around the injected site area, which is very promising to target tumors and follow biodistribution in vivo.

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Antitumor activity of CKD-602, a camptothecin derivative, in a mouse glioma model

Cited by 3 publications

References 27 publications

Combination therapy of cilengitide with belotecan against experimental glioblastoma

Combination therapy of cilengitide with belotecan against experimental glioblastoma

Current status of CPT and its analogues in the treatment of malignancies

Synthesis, Biological Evaluation, and in Vivo Imaging of the first Camptothecin–Fluorescein Conjugate

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