Skin ulceration potential of paclitaxel in a mouse skin model in vivo

Robert T Dorr, Kristi Snead, James D. Liddil

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

BACKGROUND. The antimitotic agent paclitaxel is highly active in the therapy of several tumor types, including ovarian and breast cancer. The commercial formulation (Taxol®) is supplied in a vehicle containing alcohol and the surfactant Cremophor EL® (polyethoxylated castor oil). Whereas Phase I studies did not describe extravasation necrosis, more recent case reports have suggested that paclitaxel can cause soft tissue necrosis if inadvertently extravasated. The efficacy of various antidotal maneuvers, if any, was not known. METHODS. Debaired, BALB/c mice were given intradermal (ID) injections of paclitaxel 0.3 mg, 0.6 mg, or 1.2 mg, or Cremophor EL®, 0.1 mL, into the dorsal skin. The sites were observed thrice weekly for evidence of ulceration. Perpendicular widths of skin ulcers were measured by caliper and multiplied to yield a lesion area in cm2. The lesion area multiplied by time in days was integrated by computer to yield cumulative ulceration areas in (cm2 · days). Potential pharmacologic adjuvants were injected ID after paclitaxel. These included saline (0.05 mL), albumin (0.05 mL), hyaluronidase (15 Units), and hydrocortisone (2.5 mg). Topical adjuvants included dimethylsulfoxide solution, (0.1 mL), cooling to 8-10 °C or heating to 43-44 °C for 30 minutes after ID paclitaxel. RESULTS. Dose-dependent skin ulcers that lasted 12-17 days were created with the 3 ID paclitaxel doses. The two higher paclitaxel dose levels, 0.6 mg and 1.2 mg, were selected for antidote studies. Hyaluronidase and saline were effective ID antidotes for lesions induced by the 0.6-mg paclitaxel dose, but not for the higher paclitaxel dose of 1.2 mg (P < 0.05 by analysis of variance). None of the tropical adjuvants or other ID adjuvants significantly reduced paclitaxel- induced skin ulcers in the mice. CONCLUSIONS. Paclitaxel has experimental vesicant potential in the ID mouse skin model. Clinical extravasations of paclitaxel may be treated by subcutaneous injections of hyaluronidase diluted in saline.

Original languageEnglish (US)
Pages (from-to)152-156
Number of pages5
JournalCancer
Volume78
Issue number1
DOIs
StatePublished - Jul 1 1996

Fingerprint

Paclitaxel
Skin
Skin Ulcer
Hyaluronoglucosaminidase
Antidotes
Necrosis
Antimitotic Agents
Intradermal Injections
Irritants
Subcutaneous Injections
Dimethyl Sulfoxide
Surface-Active Agents
Ovarian Neoplasms
Heating
Hydrocortisone
Albumins
Analysis of Variance
Alcohols
Breast Neoplasms

Keywords

  • antidotes
  • extravasation
  • paclitaxel infiltration
  • skin toxicity

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Skin ulceration potential of paclitaxel in a mouse skin model in vivo. / Dorr, Robert T; Snead, Kristi; Liddil, James D.

In: Cancer, Vol. 78, No. 1, 01.07.1996, p. 152-156.

Research output: Contribution to journalArticle

Dorr, Robert T ; Snead, Kristi ; Liddil, James D. / Skin ulceration potential of paclitaxel in a mouse skin model in vivo. In: Cancer. 1996 ; Vol. 78, No. 1. pp. 152-156.
@article{ff9b1a4cb58d44758472f204fb3c5c8c,
title = "Skin ulceration potential of paclitaxel in a mouse skin model in vivo",
abstract = "BACKGROUND. The antimitotic agent paclitaxel is highly active in the therapy of several tumor types, including ovarian and breast cancer. The commercial formulation (Taxol{\circledR}) is supplied in a vehicle containing alcohol and the surfactant Cremophor EL{\circledR} (polyethoxylated castor oil). Whereas Phase I studies did not describe extravasation necrosis, more recent case reports have suggested that paclitaxel can cause soft tissue necrosis if inadvertently extravasated. The efficacy of various antidotal maneuvers, if any, was not known. METHODS. Debaired, BALB/c mice were given intradermal (ID) injections of paclitaxel 0.3 mg, 0.6 mg, or 1.2 mg, or Cremophor EL{\circledR}, 0.1 mL, into the dorsal skin. The sites were observed thrice weekly for evidence of ulceration. Perpendicular widths of skin ulcers were measured by caliper and multiplied to yield a lesion area in cm2. The lesion area multiplied by time in days was integrated by computer to yield cumulative ulceration areas in (cm2 · days). Potential pharmacologic adjuvants were injected ID after paclitaxel. These included saline (0.05 mL), albumin (0.05 mL), hyaluronidase (15 Units), and hydrocortisone (2.5 mg). Topical adjuvants included dimethylsulfoxide solution, (0.1 mL), cooling to 8-10 °C or heating to 43-44 °C for 30 minutes after ID paclitaxel. RESULTS. Dose-dependent skin ulcers that lasted 12-17 days were created with the 3 ID paclitaxel doses. The two higher paclitaxel dose levels, 0.6 mg and 1.2 mg, were selected for antidote studies. Hyaluronidase and saline were effective ID antidotes for lesions induced by the 0.6-mg paclitaxel dose, but not for the higher paclitaxel dose of 1.2 mg (P < 0.05 by analysis of variance). None of the tropical adjuvants or other ID adjuvants significantly reduced paclitaxel- induced skin ulcers in the mice. CONCLUSIONS. Paclitaxel has experimental vesicant potential in the ID mouse skin model. Clinical extravasations of paclitaxel may be treated by subcutaneous injections of hyaluronidase diluted in saline.",
keywords = "antidotes, extravasation, paclitaxel infiltration, skin toxicity",
author = "Dorr, {Robert T} and Kristi Snead and Liddil, {James D.}",
year = "1996",
month = "7",
day = "1",
doi = "10.1002/(SICI)1097-0142(19960701)78:1<152::AID-CNCR21>3.0.CO;2-Y",
language = "English (US)",
volume = "78",
pages = "152--156",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "1",

}

TY - JOUR

T1 - Skin ulceration potential of paclitaxel in a mouse skin model in vivo

AU - Dorr, Robert T

AU - Snead, Kristi

AU - Liddil, James D.

PY - 1996/7/1

Y1 - 1996/7/1

N2 - BACKGROUND. The antimitotic agent paclitaxel is highly active in the therapy of several tumor types, including ovarian and breast cancer. The commercial formulation (Taxol®) is supplied in a vehicle containing alcohol and the surfactant Cremophor EL® (polyethoxylated castor oil). Whereas Phase I studies did not describe extravasation necrosis, more recent case reports have suggested that paclitaxel can cause soft tissue necrosis if inadvertently extravasated. The efficacy of various antidotal maneuvers, if any, was not known. METHODS. Debaired, BALB/c mice were given intradermal (ID) injections of paclitaxel 0.3 mg, 0.6 mg, or 1.2 mg, or Cremophor EL®, 0.1 mL, into the dorsal skin. The sites were observed thrice weekly for evidence of ulceration. Perpendicular widths of skin ulcers were measured by caliper and multiplied to yield a lesion area in cm2. The lesion area multiplied by time in days was integrated by computer to yield cumulative ulceration areas in (cm2 · days). Potential pharmacologic adjuvants were injected ID after paclitaxel. These included saline (0.05 mL), albumin (0.05 mL), hyaluronidase (15 Units), and hydrocortisone (2.5 mg). Topical adjuvants included dimethylsulfoxide solution, (0.1 mL), cooling to 8-10 °C or heating to 43-44 °C for 30 minutes after ID paclitaxel. RESULTS. Dose-dependent skin ulcers that lasted 12-17 days were created with the 3 ID paclitaxel doses. The two higher paclitaxel dose levels, 0.6 mg and 1.2 mg, were selected for antidote studies. Hyaluronidase and saline were effective ID antidotes for lesions induced by the 0.6-mg paclitaxel dose, but not for the higher paclitaxel dose of 1.2 mg (P < 0.05 by analysis of variance). None of the tropical adjuvants or other ID adjuvants significantly reduced paclitaxel- induced skin ulcers in the mice. CONCLUSIONS. Paclitaxel has experimental vesicant potential in the ID mouse skin model. Clinical extravasations of paclitaxel may be treated by subcutaneous injections of hyaluronidase diluted in saline.

AB - BACKGROUND. The antimitotic agent paclitaxel is highly active in the therapy of several tumor types, including ovarian and breast cancer. The commercial formulation (Taxol®) is supplied in a vehicle containing alcohol and the surfactant Cremophor EL® (polyethoxylated castor oil). Whereas Phase I studies did not describe extravasation necrosis, more recent case reports have suggested that paclitaxel can cause soft tissue necrosis if inadvertently extravasated. The efficacy of various antidotal maneuvers, if any, was not known. METHODS. Debaired, BALB/c mice were given intradermal (ID) injections of paclitaxel 0.3 mg, 0.6 mg, or 1.2 mg, or Cremophor EL®, 0.1 mL, into the dorsal skin. The sites were observed thrice weekly for evidence of ulceration. Perpendicular widths of skin ulcers were measured by caliper and multiplied to yield a lesion area in cm2. The lesion area multiplied by time in days was integrated by computer to yield cumulative ulceration areas in (cm2 · days). Potential pharmacologic adjuvants were injected ID after paclitaxel. These included saline (0.05 mL), albumin (0.05 mL), hyaluronidase (15 Units), and hydrocortisone (2.5 mg). Topical adjuvants included dimethylsulfoxide solution, (0.1 mL), cooling to 8-10 °C or heating to 43-44 °C for 30 minutes after ID paclitaxel. RESULTS. Dose-dependent skin ulcers that lasted 12-17 days were created with the 3 ID paclitaxel doses. The two higher paclitaxel dose levels, 0.6 mg and 1.2 mg, were selected for antidote studies. Hyaluronidase and saline were effective ID antidotes for lesions induced by the 0.6-mg paclitaxel dose, but not for the higher paclitaxel dose of 1.2 mg (P < 0.05 by analysis of variance). None of the tropical adjuvants or other ID adjuvants significantly reduced paclitaxel- induced skin ulcers in the mice. CONCLUSIONS. Paclitaxel has experimental vesicant potential in the ID mouse skin model. Clinical extravasations of paclitaxel may be treated by subcutaneous injections of hyaluronidase diluted in saline.

KW - antidotes

KW - extravasation

KW - paclitaxel infiltration

KW - skin toxicity

UR - http://www.scopus.com/inward/record.url?scp=0030014695&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030014695&partnerID=8YFLogxK

U2 - 10.1002/(SICI)1097-0142(19960701)78:1<152::AID-CNCR21>3.0.CO;2-Y

DO - 10.1002/(SICI)1097-0142(19960701)78:1<152::AID-CNCR21>3.0.CO;2-Y

M3 - Article

C2 - 8646711

AN - SCOPUS:0030014695

VL - 78

SP - 152

EP - 156

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 1

ER -