Regulatable Transgene Expression for Prevention of Chemotherapy-Induced Peripheral Neuropathy

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating complication associated with drug treatment of cancer for which there are no effective strategies of prevention or treatment. In this study, we examined the effect of intermittent expression of neurotophin-3 (NT-3) or interleukin-10 (IL-10) from replication-defective herpes simplex virus (HSV)-based regulatable vectors delivered by subcutaneous inoculation to the dorsal root ganglion (DRG) on the development of paclitaxel-induced peripheral neuropathy. We constructed two different tetracycline (tet)-on-based regulatable HSV vectors, one expressing NT-3 and the other expressing IL-10, in which the transactivator expression in the tet-on system was under the control of HSV latency-associated promoter 2 (LAP-2), and expression of the transgene was controlled by doxycycline (DOX). We examined the therapeutic effect of intermittent expression of the transgene in animals with paclitaxel-induced peripheral neuropathy modeled by intraperitoneal injection of paclitaxel (16 mg/kg) once a week for 5 weeks. Intermittent expression of either NT-3 or IL-10 3 days before and 1 day after paclitaxel administration protected animals against paclitaxel-induced peripheral neuropathy over the course of 5 weeks. These results suggest the potential of regulatable vectors for prevention of chemotherapy-induced peripheral neuropathy.

Related collections

Most cited references 47

Record: found
Abstract: found
Article: not found

Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction.

Sarah Flatters, Gary Bennett (2006)

Paclitaxel chemotherapy frequently induces neuropathic pain during and often persisting after therapy. The mechanisms responsible for this pain are unknown. Using a rat model of paclitaxel-induced painful peripheral neuropathy, we have performed studies to search for peripheral nerve pathology. Paclitaxel-induced mechano-allodynia and mechano-hyperalgesia were evident after a short delay, peaked at day 27 and finally resolved on day 155. Paclitaxel- and vehicle-treated rats were perfused on days 7, 27 and 160. Portions of saphenous nerves were processed for electron microscopy. There was no evidence of paclitaxel-induced degeneration or regeneration as myelin structure was normal and the number/density of myelinated axons and C-fibres was unaltered by paclitaxel treatment at any time point. In addition, the prevalence of ATF3-positive dorsal root ganglia cells was normal in paclitaxel-treated animals. With one exception, at day 160 in myelinated axons, total microtubule densities were also unaffected by paclitaxel both in C-fibres and myelinated axons. C-fibres were significantly swollen following paclitaxel at days 7 and 27 compared to vehicle. The most striking finding was significant increases in the prevalence of atypical (swollen and vacuolated) mitochondria in both C-fibres (1.6- to 2.3-fold) and myelinated axons (2.4- to 2.6-fold) of paclitaxel-treated nerves at days 7 and 27. Comparable to the pain behaviour, these mitochondrial changes had resolved by day 160. Our data do not support a causal role for axonal degeneration or dysfunction of axonal microtubules in paclitaxel-induced pain. Instead, our data suggest that a paclitaxel-induced abnormality in axonal mitochondria of sensory nerves contributes to paclitaxel-induced pain.

0 comments Cited 167 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms.

Gretta Armstrong, N Rosenshein, E Rowinsky … (1989)

To assess the activity of taxol in patients with advanced, progressive, and drug-refractory ovarian cancer and to delineate more clearly the toxicity of taxol in this patient population. Nonrandomized, prospective phase II trial. Forty-seven patients with drug-refractory epithelial ovarian cancer who had one or more lesions measurable in perpendicular diameters. Of these patients, 45 were evaluable for toxicity and 40 were evaluable for response. PATIENTS were treated every 22 days with varying doses of taxol (110 to 250 mg/m2 body surface) given as a 24-hour infusion with subsequent doses based on adverse effects. A premedication regimen was used to avoid acute hypersensitivity reactions. Twelve patients (30%; CI, 16% to 44%) responded to taxol for periods lasting from 3 to 15 months. The dose-limiting toxicity was myelosuppression with leukocytes affected more severely and commonly than thrombocytes or reticulocytes. Leukopenia was usually brief in duration but was associated with sepsis in 3 cases (2 fatal). Other adverse effects included myalgias, arthralgias, alopecia, diarrhea, nausea, vomiting, mucositis, and peripheral neuropathy. Rare cases of cardiac and central neurotoxicity were also noted. Taxol is an active agent in drug-refractory ovarian cancer and deserves further study in combination with other active drugs in previously untreated patients with advanced ovarian cancer.

0 comments Cited 112 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer.

F. A. Holmes, R Walters, R L Theriault … (1991)

Taxol, an antimicrotubule agent, has shown promise for efficacy in treatment of breast cancer, but severe hypersensitivity reactions led to cessation of many phase I clinical trials. Consequently, investigators and the National Cancer Institute recommended that phase I and II studies of this agent use 24-hour infusions and antiallergic medications. Using a premedication regimen effective in preventing hypersensitivity reactions, we have performed a phase II trial of taxol in patients with metastatic breast cancer. Taxol was administered to 25 patients at a dose of 250 mg/m2 by 24-hour infusion every 21 days. These patients had received only one prior chemotherapy regimen, either adjuvant to surgery or for metastatic disease; all but two had received doxorubicin. In 60% of the patients, the dominant site of disease was the viscera. All patients were assessable. In April 1991, at a median time on study of 9 months (range, 5-13+ months), the objective response rate was 56% (12% complete and 44% partial; 95% confidence interval, 35%-76%). Disease progressed in only 8% of the patients. The median number of courses of therapy was 11. Granulocytopenia was the dose-limiting toxic effect, but neutropenia with fever occurred in only 5% of 232 courses. A chronic glove-and-stocking neuropathy developed in most patients, but no allergic reactions occurred. We conclude that taxol is an active agent in the treatment of metastatic breast cancer and that it warrants continued study. Currently, we are conducting a phase I trial of taxol plus doxorubicin. Future trials should address the optimal effective dose, the optimal sequencing of combinations, mechanisms of drug resistance in tumors, and dose-limiting toxic effects (particularly cardiac toxic effects of taxol given as a single agent or in drug combinations).

0 comments Cited 92 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Zetang Wu

Journal

Journal ID (nlm-ta): Mol Ther Methods Clin Dev

Journal ID (iso-abbrev): Mol Ther Methods Clin Dev

Title: Molecular Therapy. Methods & Clinical Development

Publisher: American Society of Gene & Cell Therapy

ISSN (Electronic): 2329-0501

Publication date PMC-release: 21 June 2017

Publication date Collection: 15 September 2017

Publication date (Electronic): 21 June 2017

Volume: 6

Pages: 91-101

Affiliations

[1 ]Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA

[2 ]VA Ann Arbor Healthcare System, Ann Arbor, MI 48109, USA

[3 ]Department of Anesthesiology, Asahikawa Medical University, Higashi Asahikawa 078-8510, Japan

Author notes

[∗ ]Corresponding author: Zetang Wu, Department of Neurology, University of Michigan, Room 5238, BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA. zetang@ 123456umich.edu

Article

Publisher ID: S2329-0501(17)30079-7

DOI: 10.1016/j.omtm.2017.06.004

PMC ID: 5496212

SO-VID: 6bb0d500-e7ab-4ebd-aa9e-d7f58de16a06

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 12 January 2017

Date accepted : 16 June 2017

Comments

Comment on this article

scite_

Smart Citations

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

Most referenced authors 400

See all reference authors

- Version 1

Regulatable Transgene Expression for Prevention of Chemotherapy-Induced Peripheral Neuropathy

Read this article at

Abstract

Related collections

Tobacco Prevention & Cessation

Most cited references 47

Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction.

Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms.

Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer.

Author and article information

Contributors

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 287

Most referenced authors 400