<i>In vivo</i> Anti‐tumor Activity of a Novel Indolocarbazole Compound, J‐107088, on Murine and Human Tumors Transplanted into Mice

Arakawa, Hiroharu; Morita, Masashi; Kodera, Tsutomu; Okura, Akira; Ohkubo, Mitsuru; Morishima, Hajime; Nishimura, Susumu

doi:10.1111/j.1349-7006.1999.tb00691.x

Cited by 36 publications

(29 citation statements)

References 6 publications

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“…The results across all experiments confirmed the previously reported high margin of safety observed with edotecarin (17). In general, decreases in net body weight were comparable across treatments within a study and did not seem to differ significantly (Supplementary Table S8A).…”

Section: Resultssupporting

confidence: 85%

“…The antitumor efficacy of edotecarin, when used as a single agent, has been characterized in vitro with human cancer cells and in vivo with human tumor models in nude mice (10,15,17). For example, cytotoxic activity against a panel of 31 human cancer cells has been shown, with IC 50 values ranging from 0.0015 to 0.39 Amol/L (10,15).…”

mentioning

confidence: 99%

“…In addition, the spectrum of activity of edotecarin against human cancer cell lines was found to differ from camptothecin, doxorubicin, etoposide, and cisplatin (10). In several different human tumor xenograft models in nude mice, and using a broad range of malignancies, edotecarin when used as a single agent produced significant antitumor activity (15,17,18). Xenograft models have also been useful in preclinical systems to test the antitumor activity of the topoisomerase I inhibitors irinotecan and topotecan when used in combination with either cisplatin or 5-FU.…”

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confidence: 99%

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Antitumor Efficacy of Edotecarin as a Single Agent and in Combination with Chemotherapy Agents in a Xenograft Model

Ciomei

Croci²,

Ciavolella³

et al. 2006

Clinical Cancer Research

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The novel indolocarbazole edotecarin (J-107088, formerly ED-749) differs from other topoisomerase I inhibitors both pharmacokinetically and pharmacodynamically. In vitro, it is more potent than camptothecins and has a variable cytotoxic activity in 31 different human cancer cell lines. Edotecarin also possesses greater than additive inhibitory effects on cell proliferation when used in combination with other agents tested in vitro against various cancer cell lines. The present in vivo studies were done to extend the in vitro findings to characterize the antitumor effects of edotecarin when used either alone or in combination with other agents (i.e., 5-fluorouracil, irinotecan, cisplatin, oxaliplatin, and SU11248) in the HCT-116 human colon cancer xenograft model. Treatment effects were based on the delay in onset of an exponential growth of tumors in drugtreated versus vehicle control-treated groups. In all studies, edotecarin was active both as a single agent and in combination with other agents. Combination therapy resulted in greater than additive effects, the extent of which depended on the specific dosage regimen. Toxicity in these experiments was minimal. Of all 359 treated mice, the six that died of toxicity were in the high-dose edotecarin/oxaliplatin group. The results suggest that edotecarin may serve as effective chemotherapy of colon cancer when used as a single agent, in combination with standard regimens and other topoisomerase inhibitors or with novel agents, such as the multitargeted tyrosine kinase inhibitor SU11248.

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Section: Resultssupporting

confidence: 85%

mentioning

confidence: 99%

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confidence: 99%

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Antitumor Efficacy of Edotecarin as a Single Agent and in Combination with Chemotherapy Agents in a Xenograft Model

Ciomei

Croci²,

Ciavolella³

et al. 2006

Clinical Cancer Research

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“…13 To date, combinational treatment regimens that include PTX have been reported to be successful in targeting hormone-refractory prostate cancers in clinical trials 20 as well as in an animal study involving PC-3 xenograft models. 21 The principal mechanism of the cytotoxic action of PTX is stabilization of microtubules, which leads to mitotic arrest. 22 PTX has also been shown to have a potent inhibitory effect on angiogenesis, 23 a process that has been proposed as a target for the chemotherapeutic treatment of prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts

Takei

Kadomatsu

Goto

et al. 2006

Cancer

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Background Many professional emergency responders (ERs) who belong to the Korean National Emergency Management Agency (NEMA) have been cross‐trained and serve multiple roles. As such, firefighters and other ERs in Korea are exposed to similar occupational hazards. This study was conducted to estimate cancer morbidity in male ERs and compare that with Korean men. Methods The cohort was comprised of 33,416 male ERs working between 1980 and 2007, who were alive on December 31, 1995. Work histories were merged with the Korea National Central Cancer Registry (KNCCR) to assess cancer morbidity between 1996 and 2007. Standardized incidence ratios (SIRs) with reference to Korean men were analyzed. Results SIRs with reference to national cancer rates were not significantly decreased for overall cancer (SIR = 0.97, 95% CI = 0.90–1.08) in all ERs. However, colorectal (SIR = 1.35, 95% CI = 1.07–1.67), kidney (SIR = 1.59, 95% CI = 1.00–2.41), and bladder (SIR = 1.77, 95% CI = 1.08–2.73) cancer, and non‐Hodgkin's lymphoma (SIR = 1.81, 95% CI = 1.12–2.76) morbidities were significantly increased among all ERs. In firefighters, significantly increased cancer types were as same as those of all ERs. In non‐firefighter ERs, colorectal (SIR = 2.51, 95% CI = 1.20–4.61) and bone and articular cartilage cancers (SIR = 9.53, 95% CI = 1.07–34.41) were significantly higher than those of Korean men. Conclusions Korean firefighters showed excess morbidity in several cancer types, including colorectal and urologic cancers, and non‐Hodgkin's lymphoma, demonstrating similar trends to previous studies for firefighters conducted in other countries. Increased incidence in these cancer types suggests occupational exposure to carcinogens and shift work. Am. J. Ind. Med. 55:768–778, 2012. © 2012 Wiley Periodicals, Inc.

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“…[16] The activity of edotecarin was described by Arakawa et al in the same year, [17] and was shown to work by stabilising the DNA-topoisomerase I complex. This resulted in cells being incapable of unwinding DNA and therefore preventing them from dividing.…”

Section: Topoisomerase Inhibitorsmentioning

confidence: 99%

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

Sherer

Snape

2015

European Journal of Medicinal Chemistry

133

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HIGHLIGHTS• Brain cancer mortality rates are much higher than mortality rates for cancers of other sites. •Due to the blood brain barrier, many drugs that work on cancers of other sites do not work on brain cancers • Indoles, carbazoles and indolocarbazoles make good scaffolds for drugs to be built up around due to their rigidity, planarity and ease of synthesis. GRAPHICAL ABSTRACT ACRONYMS/INITIALISMSAML -Acute myeloid leukaemia CK2 -Casein kinase 2 CNS -Central nervous system PARP -Poly ADP ribose polymerase PDGF -Platelet-derived growth factor PKC -Protein kinase C ROS -Reactive oxygen species VEGF -Vascular endothelial growth factor ABSTRACT Tumours of the central nervous system are intrinsically more dangerous than tumours at other sites, and in particular, brain tumours are responsible for 3% of cancer deaths in the UK. Despite this, research into new therapies only receives 1% of national cancer research spend. The most common chemotherapies are temozolomide, procarbazine, carmustine, lomustine and vincristine, but because of the rapid development of chemoresistance, these drugs alone simply aren't sufficient for longterm treatment. Such poor prognosis of brain tumour patients prompted us to research new treatments for malignant glioma, and in doing so, it became apparent that aromatic heterocycles play an important part, especially the indole, carbazole and indolocarbazole scaffolds. This review highlights compounds in development for the treatment of tumours of the central nervous system which are structurally based on the indole, carbazole and indolocarbazole scaffolds, under the expectation that it will highlight new avenues for research for the development of new compounds to treat these devastating neoplasms.

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In vivo Anti‐tumor Activity of a Novel Indolocarbazole Compound, J‐107088, on Murine and Human Tumors Transplanted into Mice

Cited by 36 publications

References 6 publications

Antitumor Efficacy of Edotecarin as a Single Agent and in Combination with Chemotherapy Agents in a Xenograft Model

Antitumor Efficacy of Edotecarin as a Single Agent and in Combination with Chemotherapy Agents in a Xenograft Model

Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

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