TOXICITY STUDIES OF VP 16-213 (I) : Acute toxicity in mice, rats and rabbits

Takahashi, Norimitsu; Kadota, Toshihito; Kawano, Shigeo; Ishikawa, Katsumi; Kuroyanagi, Kohji; Hamajima, Yoshinori; Ohta, Keiko; Ohta, Satoshi; Kai, Shuichi; Kohmura, Hisashi; Takeuchi, Yukako

doi:10.2131/jts.11.supplementi_1

Cited by 3 publications

(5 citation statements)

References 3 publications

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“…In addition to severe intestinal damage, etoposide administration resulted in elevated splenic and thymic atrophy in Tdp2 Δ1–3 mice, compared to wild type mice (Figure 6C), consistent with the known hypersensitivity of these organs to this drug [32]. Histological analysis of these tissues revealed a marked reduction in the cellular content in Tdp2 Δ1–3 animals (Figure 6C, right, note the low density of dark-stained nuclei).…”

Section: Resultssupporting

confidence: 69%

“…Remarkably, we observed that TDP2 is required for resistance to TOP2-induced DNA damage not only at the cellular level, but also at the whole-organism level. Indeed, etoposide administration in Tdp2 Δ1–3 mice resulted in both increased mortality due to intestinal damage and in elevated toxicity in lymphoid tissue, established in vivo targets of etoposide [32]. TDP2 is therefore a critical factor in the cellular and physiological response to TOP2 poisons.…”

Section: Discussionmentioning

confidence: 99%

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TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo

et al. 2013

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Anticancer topoisomerase “poisons” exploit the break-and-rejoining mechanism of topoisomerase II (TOP2) to generate TOP2-linked DNA double-strand breaks (DSBs). This characteristic underlies the clinical efficacy of TOP2 poisons, but is also implicated in chromosomal translocations and genome instability associated with secondary, treatment-related, haematological malignancy. Despite this relevance for cancer therapy, the mechanistic aspects governing repair of TOP2-induced DSBs and the physiological consequences that absent or aberrant repair can have are still poorly understood. To address these deficits, we employed cells and mice lacking tyrosyl DNA phosphodiesterase 2 (TDP2), an enzyme that hydrolyses 5′-phosphotyrosyl bonds at TOP2-associated DSBs, and studied their response to TOP2 poisons. Our results demonstrate that TDP2 functions in non-homologous end-joining (NHEJ) and liberates DSB termini that are competent for ligation. Moreover, we show that the absence of TDP2 in cells impairs not only the capacity to repair TOP2-induced DSBs but also the accuracy of the process, thus compromising genome integrity. Most importantly, we find this TDP2-dependent NHEJ mechanism to be physiologically relevant, as Tdp2-deleted mice are sensitive to TOP2-induced damage, displaying marked lymphoid toxicity, severe intestinal damage, and increased genome instability in the bone marrow. Collectively, our data reveal TDP2-mediated error-free NHEJ as an efficient and accurate mechanism to repair TOP2-induced DSBs. Given the widespread use of TOP2 poisons in cancer chemotherapy, this raises the possibility of TDP2 being an important etiological factor in the response of tumours to this type of agent and in the development of treatment-related malignancy.

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Section: Resultssupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo

et al. 2013

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“…Another agent that can increase AAV vector transduction rates is etoposide, a topoisomerase inhibitor. The fact that it is currently used in cancer therapy for small cell lung cancer and that toxicity studies have already been done in rabbits and rodents (39) made this a reasonable candidate to test. Transduction by ALAPSN increased approximately 150-fold at concentrations of 20 and 40 M etoposide in cultures of primary airway epithelial cells (Fig.…”

Section: Aav Vectors Can Transduce Epithelial and Smooth Muscle Cellsmentioning

confidence: 99%

Transduction by adeno-associated virus vectors in the rabbit airway: efficiency, persistence, and readministration

Halbert

Standaert

Aitken

et al. 1997

J Virol

193

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The ability of recombinant adeno-associated virus (AAV) vectors to integrate into the host genome and to transduce nondividing cells makes them attractive as vehicles for gene delivery. In this study, we assessed the ability of several AAV vectors to transduce airway cells in rabbits by measuring marker gene expression. AAV vectors that transferred either a ␤-galactosidase (␤-gal) or a human placental alkaline phosphatase (AP) gene were delivered to one lobe of the rabbit lung by use of a balloon catheter placed under fluoroscopic guidance. We observed vector-encoded ␤-gal or AP staining almost exclusively in the epithelial and smooth muscle cells in the bronchus at the region of balloon placement. The overall efficiency of transduction in the balloon-treated bronchial epithelium was low but reached 20% in some areas. The majority of the staining was in ciliated cells but was also observed in basal cells and airway smooth muscle cells. We observed an 80-fold decrease in marker-positive epithelial cells during the 60-day period after vector infusion, whereas the number of markerpositive smooth muscle cells stayed constant. Although treatment with the topoisomerase inhibitor etoposide dramatically enhanced AAV transduction in primary airway epithelial cells in culture, treatment of rabbits did not improve transduction rates in the airway. Vector readministration failed to produce additional transduction events, which correlated with the appearance of neutralizing antibodies. These results indicate that both readministration and immune modulation will be required in the use of AAV vectors for gene therapy to the airway epithelium.

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“…A mild peripheral neuropathy was reported in 1-20% of patients receiving etoposide alone (1,4,8,18), although this finding has been challenged by others (14). The possible enhancement of vincristine-induced peripheral neuropathy by etoposide has also been questioned (12,25). A single case of etoposideinduced central nervous system toxicity, character-ized by acute dystonia, an extrapyramidal side effect, has also been reported (2).…”

Section: Introductionmentioning

confidence: 99%

“…Sensory neuropathy is not a recognized feature of etoposide-induced toxicity in experimental animals (1,(21)(22)(23)(24)(25), although ataxia has been reported in rats (23,24). Clinical (Fig.…”

Section: Introductionmentioning

confidence: 99%

Etoposide- and BMY-40481-Induced Sensory Neuropathy in Mice

et al. 1994

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The effects of high toxic doses of the anticancer drugs, etoposide and its phosphate derivative, BMY- Ultrastructurally, ganglion cell bodies had focally extensive dilation of the rough endoplasmic reticulum, mitochondrial swelling, increased numbers of phagolysosomes and prominent aggregations of microfilaments (globular filamentous bodies). Ultrastructural axonal changes occurred primarily in large, myelinated fibers and consisted of axonal swelling or loss, thinning of myelin sheaths, and a decrease in the number of organelles. This is the first report of etoposide-related sensory neuropathy in laboratory animals, a model that may be useful for the study of etoposide-related peripheral neuropathy in humans.

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TOXICITY STUDIES OF VP 16-213 (I) : Acute toxicity in mice, rats and rabbits

Cited by 3 publications

References 3 publications

TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo

TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo

Transduction by adeno-associated virus vectors in the rabbit airway: efficiency, persistence, and readministration

Etoposide- and BMY-40481-Induced Sensory Neuropathy in Mice

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