Mechanism of Action of Camptothecin

LIU, LEROY F.; Desai, Shyamal D.; LI, TSAI-KUN; Mao, Yong; Sun, Mei; Sim, Sai‐Peng

doi:10.1111/j.1749-6632.2000.tb07020.x

Cited by 419 publications

(212 citation statements)

References 51 publications

Supporting

Mentioning

198

Contrasting

Unclassified

Order By: Relevance

“…The chemotherapeutic agents used in this study cause a variety of molecular insults in DNA, including single-and doublestranded DNA breaks, inhibition of DNA/topoisomerase complex formation, and inhibition of DNA synthesis. [22][23][24][25] Given the sensitivity of NPCs from the developing brain to DNA damage, it is likely that NPCs in the adult brain may also be negatively affected by DNA damage. Small pools of NPCs persist in the adolescent and adult hippocampal subgranular and subventricular zones, where they are responsible for ongoing neurogenesis and may contribute to cognitive and behavioral function.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Neural precursor cells possess multiple p53-dependent apoptotic pathways

et al. 2006

View full text Add to dashboard Cite

Neural precursor cells (NPCs) are markedly sensitive to apoptotic insults. p53-dependent transcriptional activation of proapoptotic genes has been hypothesized to regulate NPC death in response to DNA damage. Recent studies of nonNPCs have also indicated that p53 may directly interact with Bcl-2 molecules and thereby regulate death independently of transcription. The contribution of transcription-independent p53 activation in NPC death has not been characterized. In this study, we found that apoptosis caused by chemotherapeutic agents in NPCs required p53 expression and new macromolecular synthesis. In contrast, NPC death induced by staurosporine, a broad kinase inhibitor, is regulated by p53 in the absence of macromolecular synthesis. The apoptosis effector molecules Bax and Bak, Apaf-1, and caspase-9 were shown to be downstream of p53 in both pathways. These findings indicate that p53 is in a unique position to regulate at least two distinct signaling portals that activate the intrinsic apoptotic death pathway in NPCs.

show abstract

Section: Discussionmentioning

confidence: 99%

“…24 Camptothecin binds to DNAtopoisomerase complexes and produces DNA breaks. 25 We determined that these agents also potently induced cell death in NPCs (Figure 1b and c, and data not shown). These results demonstrate that FGF2-expanded NPCs have a conserved sensitivity to a number of genotoxic agents with different mechanisms of action.…”

Section: Introductionmentioning

confidence: 88%

Neural precursor cells possess multiple p53-dependent apoptotic pathways

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Top1 is essential for the relaxation of DNA supercoiling ahead of the replication machinery [53,54]. If Top1 is inhibited either chemically (for example through the action of the chemotherapeutic drug camptothecin) or as a result of clustered ROS damage, the protein remains bound to the DNA creating a toxic single-strand break in actively replicating cells [55]. Tyrosyl DNA phosphodiesterase (Tdp1) catalyzes the hydrolysis of Top1 from the 3' terminus of DNA, resulting in a gap with a 3'phosphate and a 5'hydroxyl group at the margins [56], although there are alternative mechanisms of repair for this lesion involving Mre11 or Mus81 [57].…”

Section: Strand-breaks Generated By Topoisomerase Poisonsmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

383

374

View full text Add to dashboard Cite

Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

show abstract

“…Notably, the combinatorial therapy was more effective than CPT-11 alone only in the presence of functional NK cells (Figures 1d and e), underscoring the role of these cells in the combinatorial effect. The NK-cell-independent anti-cancer mechanism of CPT-11 has been studied extensively and is believed to involve the induction of DNA damage and subsequent apoptosis, 6 though cell-cycle-independent CPT-11 toxicity has also been reported. 7 It should be noted, however, that the effects described in this study might be common to other combinations of OVs and chemotherapy.…”

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

View full text Add to dashboard Cite

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.

show abstract

Mechanism of Action of Camptothecin

Cited by 419 publications

References 51 publications

Neural precursor cells possess multiple p53-dependent apoptotic pathways

Neural precursor cells possess multiple p53-dependent apoptotic pathways

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

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

Contact Info

Product

Resources

About