Combination therapy with irinotecan and protein kinase C inhibitors in malignant glioma

Chen, Thomas C.; Su, Susan; Fry, David W.; Liebes, Leonard

doi:10.1002/cncr.11307

Cited by 47 publications

(31 citation statements)

References 25 publications

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“…Due to its extremely short half-life, SN-38, the active metabolite of CPT-11, cannot be directly administrated in vivo; therefore, we opted to perform this study using CPT-11 both in vitro and in vivo. Moreover, it has been already shown that cancer cell lines, including glioma cell lines, express carboxylesterase activity and are able to convert CPT-11 into SN-38 (19,20). We believe that the use of CPT-11 in both in vitro and in vivo makes this study more internally consistent than using separate compounds in both tested scenarios.…”

Section: Discussionmentioning

confidence: 72%

Delta-24 Increases the Expression and Activity of Topoisomerase I and Enhances the Antiglioma Effect of Irinotecan

Gomez-Manzano¹,

Alonso²,

Yung³

et al. 2006

Clinical Cancer Research

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Purpose: In this study, we sought to determine whether Delta-24 could sensitize glioma cells to the topoisomerase I inhibitor irinotecan (CPT-11) and to identify the mechanisms underlying this enhanced anticancer effect. Experimental Design: We used human glioblastoma cell lines for the in vitro studies. The expression of topoisomerase I was determined in Western blot analyses, and topoisomerase I activity was determined by measuring the relaxation of a supercoiled DNA. The cell cycle distribution of cells was determined by flow cytometry analysis of the cellular DNA content. Cell viability was quantified by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Tissue culture infection dose assays were used to quantitate adenovirus replication. For the in vivo studies, athymic mice received intracranial/intratumoral injections of Delta-24 in combination with CPT-11, after which animal survival was monitored. Results: Delta-24 infection caused human glioma cells to accumulate in the S phase and induced the expression and activity of topoisomerase I as shown by Western blot and in vitro enzymatic activity assays. Further, we showed that the sequential administration of Delta-24 and CPT-11to human glioma cell cultures potentiated the CPT-11-mediated anticancer effect in vitro without modifying the replicative phenotype of the oncolytic adenovirus. In vivo experiments showed that the single intratumoral administration of Delta-24 to intracranially implanted human glioma xenografts followed by the systemic administration of CPT-11resulted in significantly prolonged animal survival. Conclusions: The combination of Delta-24 treatment with CPT-11showed an enhanced anticancer effect, which suggests that the interaction between adenoviral and human proteins can be exploited in rational anticancer therapies comprising replication-competent adenoviruses and conventional chemotherapeutic agents.Tumor-selective replication is one of the most relevant advances in adenovirus-based anticancer therapies. The oncolytic virus is itself capable of lysing the infected tumor cell to eradicate or reduce tumor mass. Replication amplifies the input dose of the oncolytic virus and helps disseminate the agent to adjacent tumor cells. We have described previously such a conditionally replicative adenovirus, called Delta-24, which expresses a mutant E1A protein that is unable to bind to Rb (1). Because of this inability to bind to Rb, Delta-24 behaves like a wild-type adenovirus in cancer cells but does not replicate efficiently in nondividing normal cells. It has been reported that adenoviruses infect primarily quiescent cells and then induce them to enter the S phase of the cell cycle so that viral DNA synthesis can occur (2, 3). This ability to induce quiescent cells to enter the S phase makes these viruses attractive for use with agents, such as topoisomerase I inhibitors, which target cells in the S phase. Of particular interest, Delta-24 induces the accumulation of infected cancer cells in the S phase (1).Previ...

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Section: Discussionmentioning

confidence: 72%

Delta-24 Increases the Expression and Activity of Topoisomerase I and Enhances the Antiglioma Effect of Irinotecan

Gomez-Manzano¹,

Alonso²,

Yung³

et al. 2006

Clinical Cancer Research

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“…In studies, SN-38 has led to decreased concentration of the antiapoptotic protein Bcl-2 and increased expression of the proapoptotic protein Bax. [25][26][27] Resistance to irinotecan and SN-38 is likely mediated by production of IL-1 beta, with activation of NF-kB, a key transcriptional factor that inhibits the apoptotic response. 28,29 SN-38 is further metabolized in the liver to an inactive metabolite, SN-38 glucuronide.…”

Section: Irinotecan: a New Therapeutic Optionmentioning

confidence: 99%

“…24 Glioma cells can convert irinotecan to SN-38 directly. 25 Increased SN-38 concentrations induce cytotoxic changes morphologically, decrease proliferation, and increase cytotoxicity. 25 The mechanism of cytotoxicity is apoptosis.…”

Section: Irinotecan: a New Therapeutic Optionmentioning

confidence: 99%

“…25 Increased SN-38 concentrations induce cytotoxic changes morphologically, decrease proliferation, and increase cytotoxicity. 25 The mechanism of cytotoxicity is apoptosis. In studies, SN-38 has led to decreased concentration of the antiapoptotic protein Bcl-2 and increased expression of the proapoptotic protein Bax.…”

Section: Irinotecan: a New Therapeutic Optionmentioning

confidence: 99%

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Experience with irinotecan for the treatment of malignant glioma

Vredenburgh¹,

Desjardins²,

Reardon³

et al. 2009

Neuro-Oncology

152

122

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Malignant glioma is the most commonly occurring primary malignant brain tumor. It is difficult to treat and is usually associated with an inexorable, rapidly fatal clinical course. Chemotherapy, radiotherapy, and surgical excision are core components in the management of malignant glioma. However, chemotherapy, even with the most active regimens currently available, achieves only modest improvement in overall survival. Novel agents and new approaches to therapy are required to improve clinical outcomes. Irinotecan, a first-line treatment for metastatic colorectal cancer and an agent with high activity against solid tumors of the gastrointestinal tract, is an inhibitor of topoisomerase I, a critical enzyme needed for DNA transcription. Irinotecan crosses the blood-brain barrier and, in preclinical investigations, has demonstrated cytotoxic activity against central nervous system tumor xenografts. Its antitumor activity has also been demonstrated against glioblastoma cells with multidrug resistance. Studies in adult and pediatric patients with recurrent, intractable malignant glioma have evaluated irinotecan as monotherapy and in combination with other agents, including temozolomide, carmustine, thalidomide, and bevacizumab. Studies of irinotecan in combination with other medications, particularly temozolomide and bevacizumab, have yielded promising results. Irinotecan monotherapy has demonstrated efficacy; however, its efficacy appears to be enhanced when used in combination with other chemotherapeutic agents. When administered concurrently with enzyme-inducing antiepileptic drugs, the dosage must be increased to compensate for enhanced cytochrome CY3A4/5 enzyme activity. Toxicities associated with irinotecan have been manageable; the most important dose-limiting toxicities are neutropenia and diarrhea. Irinotecan-based chemotherapy of malignant glioma merits further study.

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“…Recently there have been a number of reports demonstrating synergistic actions of topo I inhibitors and PKC inhibitors suggesting a potentially useful drug combination [40][41][42] .…”

Section: Karenitecin Treatment Alters the Levels Of Pkcmentioning

confidence: 99%

Karenitecin (BNP1350) radiosensitizes glioma cells with an associated increase in caspase activation and reactive oxygen species.

Robins¹

2017

J Neurol Neuromedicine

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The prognosis for patients with high-grade glioma remains dismal illustrating the need for the development of chemotherapeutic strategies intended to synergize with treatment modalities of proven efficacy such as radiation therapy. Karenitecin, (BNP1350,7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin), is a semisynthetic, orally administrable camptothecin, with physiochemical properties favoring increased accumulation of active drug within the central nervous system. This study was initiated to determine whether Karenitecin could potentiate radiosensitivity in T98G and MO59K glioma cell lines. Using clinically relevant doses of each agent, it was demonstrated that Karenitecin pretreatment significantly enhances radiosensitivity and was shown to be synergistic by isobolographic analysis. Karenitecin treatment resulted in a transient arrest in the G 2 /M phase of the cell cycle with an associated increase in expression of cyclin B1. It was further demonstrated that Karenitecin treatment results in activation of caspases, generation of reactive oxygen species, collapse of the mitochondrial membrane potential and inhibition of total protein kinase C, all of which could enhance radiosensitivity. These in vitro data suggest that Karenitecin has potential as a radiosensitizer in the treatment of malignant glioma.

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Combination therapy with irinotecan and protein kinase C inhibitors in malignant glioma

Cited by 47 publications

References 25 publications

Delta-24 Increases the Expression and Activity of Topoisomerase I and Enhances the Antiglioma Effect of Irinotecan

Delta-24 Increases the Expression and Activity of Topoisomerase I and Enhances the Antiglioma Effect of Irinotecan

Experience with irinotecan for the treatment of malignant glioma

Karenitecin (BNP1350) radiosensitizes glioma cells with an associated increase in caspase activation and reactive oxygen species.

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