Support of a free radical mechanism for enhanced antitumor efficacy of the microtubule disruptor OXi4503

Lori Rice, Christine Pampo, Sharon Lepler, Amyn Mohammed Rojiani, Dietmar W. Siemann

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Unlike normal blood vessels, the unique characteristics of an expanding, disorganized and leaky tumor vascular network can be targeted for therapeutic gain by vascular disrupting agents (VDAs), which promote rapid and selective collapse of tumor vessels, causing extensive secondary cancer cell death. A hallmark observation following VDA treatment is the survival of neoplastic cells at the tumor periphery. However, comparative studies with the second generation tubulin-binding VDA OXi4503 indicate that the viable rim of tumor tissue remaining following treatment with this agent is significantly smaller than that seen for the lead VDA, combretastatin. OXi4503 is the cis-isomer of CA1P and it has been speculated that this agent's increased antitumor efficacy may be due to its reported metabolism to orthoquinone intermediates leading to the formation of cytotoxic free radicals. To examine this possibility in situ, KHT sarcoma-bearing mice were treated with either the cis- or trans-isomer of CA1P. Since both isomers can form quinone intermediates but only the cis-isomer binds tubulin, such a comparison allows the effects of vascular collapse to be evaluated independently from those caused by the reactive hydroxyl groups. The results showed that the cis-isomer (OXi4503) significantly impaired tumor blood flow leading to secondary tumor cell death and > 95% tumor necrosis 24. h post drug exposure. Treatment with the trans-isomer had no effect on these parameters. However, the combination of the trans-isomer with combretastatin increased the antitumor efficacy of the latter agent to near that of OXi4503. These findings indicate that while the predominant in vivo effect of OXi4503 is clearly due to microtubule collapse and vascular shut-down, the formation of toxic free radicals likely contributes to its enhanced potency.

Original languageEnglish (US)
Pages (from-to)44-51
Number of pages8
JournalMicrovascular Research
Volume81
Issue number1
DOIs
StatePublished - Jan 1 2011

Fingerprint

Microtubules
Isomers
Free Radicals
Blood Vessels
Tumors
Neoplasms
Cell death
Tubulin
Bearings (structural)
Cell Death
Poisons
Blood vessels
Oxi 4503
Metabolism
Hydroxyl Radical
Sarcoma
Antineoplastic Agents
Blood
Cells
Cell Survival

Keywords

  • Combretastatin
  • Endothelial cells
  • Magnetic resonance imaging
  • OXi4503
  • Tubulin-binding agents
  • Vascular disrupting agents
  • Viable rim

ASJC Scopus subject areas

  • Biochemistry
  • Cardiology and Cardiovascular Medicine
  • Cell Biology

Cite this

Support of a free radical mechanism for enhanced antitumor efficacy of the microtubule disruptor OXi4503. / Rice, Lori; Pampo, Christine; Lepler, Sharon; Rojiani, Amyn Mohammed; Siemann, Dietmar W.

In: Microvascular Research, Vol. 81, No. 1, 01.01.2011, p. 44-51.

Research output: Contribution to journalArticle

Rice, Lori ; Pampo, Christine ; Lepler, Sharon ; Rojiani, Amyn Mohammed ; Siemann, Dietmar W. / Support of a free radical mechanism for enhanced antitumor efficacy of the microtubule disruptor OXi4503. In: Microvascular Research. 2011 ; Vol. 81, No. 1. pp. 44-51.
@article{d68d7a5e615e4d9f912b6ec4c6f97831,
title = "Support of a free radical mechanism for enhanced antitumor efficacy of the microtubule disruptor OXi4503",
abstract = "Unlike normal blood vessels, the unique characteristics of an expanding, disorganized and leaky tumor vascular network can be targeted for therapeutic gain by vascular disrupting agents (VDAs), which promote rapid and selective collapse of tumor vessels, causing extensive secondary cancer cell death. A hallmark observation following VDA treatment is the survival of neoplastic cells at the tumor periphery. However, comparative studies with the second generation tubulin-binding VDA OXi4503 indicate that the viable rim of tumor tissue remaining following treatment with this agent is significantly smaller than that seen for the lead VDA, combretastatin. OXi4503 is the cis-isomer of CA1P and it has been speculated that this agent's increased antitumor efficacy may be due to its reported metabolism to orthoquinone intermediates leading to the formation of cytotoxic free radicals. To examine this possibility in situ, KHT sarcoma-bearing mice were treated with either the cis- or trans-isomer of CA1P. Since both isomers can form quinone intermediates but only the cis-isomer binds tubulin, such a comparison allows the effects of vascular collapse to be evaluated independently from those caused by the reactive hydroxyl groups. The results showed that the cis-isomer (OXi4503) significantly impaired tumor blood flow leading to secondary tumor cell death and > 95{\%} tumor necrosis 24. h post drug exposure. Treatment with the trans-isomer had no effect on these parameters. However, the combination of the trans-isomer with combretastatin increased the antitumor efficacy of the latter agent to near that of OXi4503. These findings indicate that while the predominant in vivo effect of OXi4503 is clearly due to microtubule collapse and vascular shut-down, the formation of toxic free radicals likely contributes to its enhanced potency.",
keywords = "Combretastatin, Endothelial cells, Magnetic resonance imaging, OXi4503, Tubulin-binding agents, Vascular disrupting agents, Viable rim",
author = "Lori Rice and Christine Pampo and Sharon Lepler and Rojiani, {Amyn Mohammed} and Siemann, {Dietmar W.}",
year = "2011",
month = "1",
day = "1",
doi = "10.1016/j.mvr.2010.10.003",
language = "English (US)",
volume = "81",
pages = "44--51",
journal = "Microvascular Research",
issn = "0026-2862",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Support of a free radical mechanism for enhanced antitumor efficacy of the microtubule disruptor OXi4503

AU - Rice, Lori

AU - Pampo, Christine

AU - Lepler, Sharon

AU - Rojiani, Amyn Mohammed

AU - Siemann, Dietmar W.

PY - 2011/1/1

Y1 - 2011/1/1

N2 - Unlike normal blood vessels, the unique characteristics of an expanding, disorganized and leaky tumor vascular network can be targeted for therapeutic gain by vascular disrupting agents (VDAs), which promote rapid and selective collapse of tumor vessels, causing extensive secondary cancer cell death. A hallmark observation following VDA treatment is the survival of neoplastic cells at the tumor periphery. However, comparative studies with the second generation tubulin-binding VDA OXi4503 indicate that the viable rim of tumor tissue remaining following treatment with this agent is significantly smaller than that seen for the lead VDA, combretastatin. OXi4503 is the cis-isomer of CA1P and it has been speculated that this agent's increased antitumor efficacy may be due to its reported metabolism to orthoquinone intermediates leading to the formation of cytotoxic free radicals. To examine this possibility in situ, KHT sarcoma-bearing mice were treated with either the cis- or trans-isomer of CA1P. Since both isomers can form quinone intermediates but only the cis-isomer binds tubulin, such a comparison allows the effects of vascular collapse to be evaluated independently from those caused by the reactive hydroxyl groups. The results showed that the cis-isomer (OXi4503) significantly impaired tumor blood flow leading to secondary tumor cell death and > 95% tumor necrosis 24. h post drug exposure. Treatment with the trans-isomer had no effect on these parameters. However, the combination of the trans-isomer with combretastatin increased the antitumor efficacy of the latter agent to near that of OXi4503. These findings indicate that while the predominant in vivo effect of OXi4503 is clearly due to microtubule collapse and vascular shut-down, the formation of toxic free radicals likely contributes to its enhanced potency.

AB - Unlike normal blood vessels, the unique characteristics of an expanding, disorganized and leaky tumor vascular network can be targeted for therapeutic gain by vascular disrupting agents (VDAs), which promote rapid and selective collapse of tumor vessels, causing extensive secondary cancer cell death. A hallmark observation following VDA treatment is the survival of neoplastic cells at the tumor periphery. However, comparative studies with the second generation tubulin-binding VDA OXi4503 indicate that the viable rim of tumor tissue remaining following treatment with this agent is significantly smaller than that seen for the lead VDA, combretastatin. OXi4503 is the cis-isomer of CA1P and it has been speculated that this agent's increased antitumor efficacy may be due to its reported metabolism to orthoquinone intermediates leading to the formation of cytotoxic free radicals. To examine this possibility in situ, KHT sarcoma-bearing mice were treated with either the cis- or trans-isomer of CA1P. Since both isomers can form quinone intermediates but only the cis-isomer binds tubulin, such a comparison allows the effects of vascular collapse to be evaluated independently from those caused by the reactive hydroxyl groups. The results showed that the cis-isomer (OXi4503) significantly impaired tumor blood flow leading to secondary tumor cell death and > 95% tumor necrosis 24. h post drug exposure. Treatment with the trans-isomer had no effect on these parameters. However, the combination of the trans-isomer with combretastatin increased the antitumor efficacy of the latter agent to near that of OXi4503. These findings indicate that while the predominant in vivo effect of OXi4503 is clearly due to microtubule collapse and vascular shut-down, the formation of toxic free radicals likely contributes to its enhanced potency.

KW - Combretastatin

KW - Endothelial cells

KW - Magnetic resonance imaging

KW - OXi4503

KW - Tubulin-binding agents

KW - Vascular disrupting agents

KW - Viable rim

UR - http://www.scopus.com/inward/record.url?scp=78650826753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650826753&partnerID=8YFLogxK

U2 - 10.1016/j.mvr.2010.10.003

DO - 10.1016/j.mvr.2010.10.003

M3 - Article

VL - 81

SP - 44

EP - 51

JO - Microvascular Research

JF - Microvascular Research

SN - 0026-2862

IS - 1

ER -