High-dose Carboplatin in Combination with Etoposide (JET Regimen) for Childhood Brain Tumors

Castello, Manuel A.; Clerico, Aldo; Deb, Giovanni; Dominici, Carlo; Fidani, Paola; Donfrancesco, Alberto

doi:10.1097/00043426-199023000-00008

Cited by 61 publications

(26 citation statements)

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“…Our func tional assessment of the nystagmus response indicates that the vestibulotoxic effect of car boplatin occurs within 6 h following intrave nous administration and achieves its maxi mum effect by 1 day after injection. These rapid changes in vestibular function could conceivably contribute to the intense nausea and vomiting associated with the use of plati num-based chemotherapeutic agents [15,16]. Ongoing experiments currently underway in our laboratory also indicate that carboplatin can cause functional deficits in the auditory nerve within the first 24 li of carboplatin treatment.…”

Section: Discussionmentioning

confidence: 88%

“…Some of the large vacuoles ( fig. 5-7) surrounding the nucleus during later stages of degeneration may be due to the swollen endoplasmic reticulum: how ever, more precise identification of these structures would require specific cytochemical markers [ 15,17], Consistent with earlier reports, our results indicate that the type-1 hair cells in the central region of the crista and the striola of the macula arc considerably more vulnerable to the ototoxic effects of carboplatin than type-I I hair cells [3]. Furthermore, the onset of dam age and the amount of hair cell loss was more severe in the crista ampullaris of the semicir cular canal than in the macula of the utricle and saccule as noted previously [3], Some vacuoles were seen in typc-11 hair cells several days after carboplatin treatment, but their size and number were much less than seen in type-I hair cells.…”

Section: Discussionmentioning

confidence: 99%

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Early Damage in the Chinchilla Vestibular Sensory Epithelium from Carboplatin

1997

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Carboplatin, a second-generation platinum drug used in the treatment of cancer, can damage the hair cells in the vestibular system; however, little is known about the time course of its vestibulotoxic effects. The present study examined the acute vestibulotoxic effects of carboplatin (50 mg/kg) in the chinchilla. The duration of the nystagmus response evoked by cold caloric stimulation was significantly reduced 6 h following carboplatin treatment and showed a maximum, permanent reduction of approximately 50% by 24 h after injection. Light-microscopic observations at 6 h subsequent to injection revealed swollen afferent dendrites beneath type-I hair cells and the appearance of small vacuoles within the type-I hair cells; these changes were most pronounced in the crista ampullaris of the semicircular canals compared to the maculae of the utricle and saccule. Many mitochondria were swollen and partially depleted of their membranous infoldings. The mitochondrial abnormalities tended to be somewhat more severe in the hair cells than in their afferent terminals. The structural abnormalities in the mitochondria were more severe at 24 h following injection resulting in the appearance of larger and more numerous vacuoles in the hair cells. By 3 days after injection, many type-I hair cells were filled with large vacuoles which often caused severe distortion of the nucleus and disruption of the plasma membrane. Small vacuoles were occasionally observed in type-II hair cells, mainly in the crista ampullaris. These results indicate that the vestibulotoxic effects of carboplatin occur quite rapidly and cause significant disruption of the mitochondria in hair cells and their afferent terminals.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Early Damage in the Chinchilla Vestibular Sensory Epithelium from Carboplatin

1997

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“…A number of pre-clinical studies have shown carboplatin to have significant cytotoxic effects against glioma (Wolff et al, 1999;Leuraud et al, 2004). However, clinical application of carboplatin to the treatment of glioma has proven disappointing, despite high-dose intravenous and intra-arterial administration (Follezou et al, 1989;Castello et al, 1990;Stewart et al, 1992;Larner et al, 1995;Cloughesy et al, 1997;Qureshi et al, 2001;Silvani et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

A novel implantable catheter system with transcutaneous port for intermittent convection-enhanced delivery of carboplatin for recurrent glioblastoma

et al. 2014

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Context: Inadequate penetration of the blood-brain barrier (BBB) by systemically administered chemotherapies including carboplatin is implicated in their failure to improve prognosis for patients with glioblastoma. Convection-enhanced delivery (CED) of carboplatin has the potential to improve outcomes by facilitating bypass of the BBB.Objective: We report the first use of an implantable CED system incorporating a novel transcutaneous bone-anchored port (TBAP) for intermittent CED of carboplatin in a patient with recurrent glioblastoma.Materials and methods: The CED catheter system was implanted using a robot-assisted surgical method. Catheter targeting accuracy was verified by performing intra-operative O-arm imaging. The TBAP was implanted using a skin-flap dermatome technique modeled on bone-anchored hearing aid surgery. Repeated infusions were performed by attaching a needle administration set to the TBAP. Drug distribution was monitored with serial real-time T2-weighted magnetic resonance imaging (MRI).Results: All catheters were implanted to within 1.5 mm of their planned target. Intermittent infusions of carboplatin were performed on three consecutive days and repeated after one month without the need for further surgical intervention. Infused volumes of 27.9 ml per day were well tolerated, with the exception of a single seizure episode. Follow-up MRI at eight weeks demonstrated a significant reduction in the volume of tumor enhancement from 42.6 ml to 24.6 ml, and was associated with stability of the patient's clinical condition.Conclusion: Reduction in the volume of tumor enhancement indicates that intermittent CED of carboplatin has the potential to improve outcomes in glioblastoma. The novel technology described in this report make intermittent CED infusion regimes an achievable treatment strategy.

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“…This is quite relevant since cisplatin is frequently used in the treatment of medulloblastoma patients. [27][28][29][30] Detailed analysis of the DNA repair of DSBs indicates that homologous recombination-directed DNA repair (HRR) is significantly impaired while NHEJ is practically unaffected in JCV T-antigen expressing murine medulloblastoma cell lines. Although we are unable to detect any direct interaction between JCV T-antigen and DNA repair proteins, we find IRS-1 at the sites of damaged DNA.…”

mentioning

confidence: 99%

IRS‐1–Rad51 nuclear interaction sensitizes JCV T‐antigen positive medulloblastoma cells to genotoxic treatment

Trojanek

Croul

et al. 2006

Intl Journal of Cancer

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The large T-antigen from human polyomavirus JC (JCV T-antigen) is suspected to play a role in malignant transformation. Previously, we reported that JCV T-antigen requires the presence of a functional insulin-like growth factor I receptor (IGF-IR) for transformation of fibroblasts and for survival of medulloblastoma cell lines; that IGF-IR is phosphorylated in medulloblastoma biopsies and that JCV T-antigen inhibits homologous recombinationdirected DNA repair, causing accumulation of mutations. Here we are evaluating whether JCV T-antigen positive and negative mouse medulloblastoma cell lines, which significantly differ in their tumorigenic properties, are also different in their abilities to repair double strand breaks of DNA (DSBs). Our results show that despite much stronger tumorigenic potential, JCV T-antigen positive medulloblastoma cells are more sensitive to genotoxic agents (cisplatin and c-irradiation). Subsequent analysis of DNA repair of DSBs indicated that homologous recombination-directed DNA repair (HRR) was selectively attenuated in JCV T-antigen positive medulloblastoma cells. JCV T-antigen did not affect HRR directly. In the presence of JCV T-antigen, insulin receptor substrate 1 (IRS-1) translocated to the nucleus where it co-localized with Rad51, possibly attenuating HRR. ' 2006 Wiley-Liss, Inc.

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High-dose Carboplatin in Combination with Etoposide (JET Regimen) for Childhood Brain Tumors

Cited by 61 publications

References 0 publications

Early Damage in the Chinchilla Vestibular Sensory Epithelium from Carboplatin

Early Damage in the Chinchilla Vestibular Sensory Epithelium from Carboplatin

A novel implantable catheter system with transcutaneous port for intermittent convection-enhanced delivery of carboplatin for recurrent glioblastoma

IRS‐1–Rad51 nuclear interaction sensitizes JCV T‐antigen positive medulloblastoma cells to genotoxic treatment

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