Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity

Xu, Yiqing; Villalona‐Calero, Miguel A.

doi:10.1093/annonc/mdf337

Cited by 336 publications

(262 citation statements)

References 61 publications

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“…The combined treatment also reduced tumour cell proliferation. In agreement with previous data (Ohwada et al, 1996;Xu and Villalona-Calero, 2002), we found that SN-38 alone markedly inhibited HT-29 cell proliferation by arresting cells mainly at the G2/M phase and, to a lesser extent, at the S phase. AS602868 for its part only induced a modest arrest at the S phase, but in combination with SN38 increased the number of cells in both S and G2/M phases.…”

Section: Discussionsupporting

confidence: 93%

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

et al. 2008

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NF-kB interferes with the effect of most anti-cancer drugs through induction of anti-apoptotic genes. Targeting NF-kB is therefore expected to potentiate conventional treatments in adjuvant strategies. Here we used a pharmacological inhibitor of the IKK2 kinase (AS602868) to block NF-kB activation. In human colon cancer cells, inhibition of NF-kB using 10 mM AS602868 induced a 30 -50% growth inhibitory effect and strongly enhanced the action of SN-38, the topoisomerase I inhibitor and CPT-11 active metabolite. AS602868 also potentiated the cytotoxic effect of two other antineoplasic drugs: 5-fluorouracil and etoposide. In xenografts experiments, inhibition of NF-kB potentiated the antitumoural effect of CPT-11 in a dose-dependent manner. Eighty-five and 75% decreases in tumour size were observed when mice were treated with, respectively, 20 or 5 mg kg À1 AS602868 associated with 30 mg kg À1 CPT-11 compared to 47% with CPT-11 alone. Ex vivo tumour analyses as well as in vitro studies showed that AS602868 impaired CPT-11-induced NF-kB activation, and enhanced tumour cell cycle arrest and apoptosis. AS602868 also enhanced the apoptotic potential of TNFa on HT-29 cells. This study is the first demonstration that a pharmacological inhibitor of the IKK2 kinase can potentiate the therapeutic efficiency of antineoplasic drugs on solid tumours.

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Section: Discussionsupporting

confidence: 93%

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

et al. 2008

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“…In our study, we have shown that proteasome-mediated TOP1 downregulation is one part of the TIP pathway possibly downstream of transcription collision between RNA polymerase and TOP1cc. Interestingly, Bortezomib, the first proteasome inhibitor tested in clinical trial, has the greatest efficacy when combined with other chemotherapeutic agents including the TOP1-targeting drug irinotecan at its low dosage [33,34]. Consistently, we have also reported that the proteasome inhibitor MG132 sensitized cells to CPT-induced cytotoxicity and apoptosis [23].…”

Section: The Cellular Processing Pathways Of Top1cc and Implicationsmentioning

confidence: 76%

Cellular processing determinants for the activation of damage signals in response to topoisomerase I-linked DNA breakage

et al. 2010

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“…Mechanisms of tumor resistance to the NK-cell-independent anti-cancer effects of CPT-11 have been reviewed previously. 10 Resistance to NK cell cytotoxicity can also develop, but may be overcome by using immunotherapies that activate multiple types of immune cells, and therefore utilize non-overlapping mechanisms to destroy the tumor cells. We have recently found that Sindbis/IL-12 induces the IFNg-dependent activation of peritoneal macrophages in ES2-bearing mice.…”

Section: Resultsmentioning

confidence: 99%

The role of natural killer cells in combinatorial anti-cancer therapy using Sindbis viral vectors and irinotecan

Granot¹,

Meruelo²

2012

Cancer Gene Ther

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Oncolytic viruses (OVs) have shown great anti-cancer potential in animal models, but only modest success in early clinical trials. A better understanding of the mechanisms underlining OV efficacy is needed to resolve this discrepancy. In the clinic, OV therapy will likely be combined with traditional chemotherapy, underscoring the need to also evaluate the interactions between these therapeutic modalities. Here we show that combining Sindbis viral vector therapy with the topoisomerase inhibitor irinotecan (CPT-11) results in the long-term survival of about 35% of SCID mice bearing aggressively growing ES2 human ovarian cancer. Single-agent treatments did not result in long-term survival. Flow cytometry analysis, bioluminescent imaging and survival experiments revealed that Sindbis and CPT-11 utilize non-overlapping natural killer (NK)-cell-dependent and -independent anti-cancer mechanisms, respectively. Notably, the combinatorial therapy was only effective in the presence of NK cells. These results highlight the hidden role of immune cell activation in combinatorial cancer therapy involving OVs and provide a potential method for tackling tumor cell resistance to cancer therapy while limiting treatment-related side effects.Cancer Gene Therapy (2012) 19, 588--591; doi:10.1038/cgt.2012.33; published online 8 June 2012Keywords: irinotecan; NK cells; ovarian cancer; Sindbis MATERIALS AND METHODS MiceAll animal experiments were performed in accordance with NIH and institutional guidelines. In this study, we used 6--12-week-old female 'ES1/ SCID' mice from our own colony, which were generated by breeding C.B-17-SCID mice with Ces1c Foxn1/J mice (The Jackson Laboratory, Bar Harbor, ME), and were selected for the absence of T and B cells and for a deficiency in plasma esterase activity. CPT-11 can be cleaved into the more potent topoisomerase inhibitor SN-38 by mouse plasma esterase, of which there is no human homolog. Therefore, plasma esterase-deficient mice (ES1/SCID mice) more closely resemble the human condition for experiments utilizing CPT-11. 1 Cell linesBaby hamster kidney and human ovarian carcinoma (ES2) cells were obtained from the American Type Culture Collection. Baby hamster kidney cells were maintained in minimum essential a-modified media (aMEM, Mediatech) with 10% fetal calf serum. ES2 cells were cultured in McCoy's 5A medium (Mediatech, Herndon, VA, USA) supplemented with 10% fetal calf serum. All basal media were supplemented with 100 mg ml À1 of penicillin--streptomycin (Mediatech) and 0.5 mg ml À1 of amphotericin B (Mediatech). ES2/Fluc cells were derived from the ES2 cell line by stable transfection of a plasmid, pIRES2-Fluc/EGFP, as previously described. 2 Sindbis vector production Sindbis vectors (Sin/LacZ and Sin/IL-12) were produced as previously described. 2 CPT-11 formulationIrinotecan hydrochloride injection (CPT-11) was obtained from Teva Parenteral Medicines (Irvine, CA) and was diluted in phosphate-buffered saline (PBS) for mouse injections.

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Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity

Cited by 336 publications

References 61 publications

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

Cellular processing determinants for the activation of damage signals in response to topoisomerase I-linked DNA breakage

The role of natural killer cells in combinatorial anti-cancer therapy using Sindbis viral vectors and irinotecan

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