Effects of Growth Factors on Doxorubicin-Induced Skin Necrosis: Documentation of Histomorphological Alterations and Early Treatment by GM-CSF and G-CSF

Abstract

Extravasation of vesicant antineoplastic agents such as doxorubicin into the skin or subcutaneous tissues may result in loss of the full thickness of the skin or underlying structures. Several treatment methods have been advocated but none has demonstrated any superiority to the others. The authors designed a controlled animal study in 88 rats to test three methods of early treatment of extravasation of the vesicant antineoplastic agent doxorubicin. The first step of the study included 48 Sprague-Dawley rats. All animals received intradermal injections of 1 mg doxorubicin superficially to the panniculus carnosus in the dorsum. The rats were then divided into four groups of 12 rats each, as follows: group 1, no treatment; group 2, immediate intradermal injection of 0.1 ml saline to the same site; group 3, immediate intradermal injection of 10 microg granulocyte macrophage-colony stimulating factor (GM-CSF) in 0.1 ml saline to the same site; group 4, immediate intradermal injection of 10 microg granulocyte-colony stimulating factor (G-CSF) in 0.1 ml saline to the same site. During the next 6 weeks the rats were observed for the development of necrosis. Ulcers developed and reached maximum size two weeks after the injections. The largest ulcers according to area were observed in group 1 and the mean value was 21.25 mm (p < 0.05). Although wound areas were significantly smaller in the saline group than in the control group and the mean value was 7.58 mm (p < 0.05), the smallest lesions were observed in groups 3 and 4, and the mean values were 1.08 mm and 0.83 mm respectively (p < 0.05). There was statistically no difference with regard to mean ulcer area between groups 3 and 4. During the second step of the experiment, the remaining 40 Sprague-Dawley rats were used. Groups containing 10 rats each were designed similarly after all animals received intradermal injections of 1 mg doxorubicin into the back. On the 10th day after the injection, the entire area of the ulcer together with the underlying panniculus carnosus was excised for pathological examination and for determination of glucose 6-phosphate dehydrogenase (G6PD) activity. On microscopic examination, the extravasated ulcer consisted of a large area of ischemic necrosis. There was marked damage to small blood vessels in the form of fibrinoid necrosis and vasculitis. Injured vessel counts were higher in the control group (group 1; p < 0.05). No difference was observed in G6PD activity between the groups. The authors conclude that both saline and tissue growth factors (GM-CSF and G-CSF) are useful for the early treatment of doxorubicin extravasation; however, GM-CSF and G-CSF are more beneficial.

The Effect of Carnitine on Doxorubicin Induced Extravasation Injuries: A New Treatment Method for Extravasation Injuries

“…9,14 However, no agent could be suggested for clinic use. Thus, we evaluated the effects of carnitine, a potent antioxidant, on doxorubicin induced extravasation.…”

“…All these agents has different effect mechanisms such as scavenging free oxygen radicals, reducing inflamatory responce, increasing new vessles , inhibiting coagulation, increasing endothelial cell proliferation and angiogenesis. 6,8,15,16 Several clinical and surgical approaches have been tested as well such as VAC, hyperbaric oxygen therapy and surgical intervention. [17][18][19] We tested carnitine for doxorubicin induced extravasation injuries in our study.…”

“…7 Several studies were performed on doxorubicin extravasation injuries, yet there is no treatment developed that we can consider as ideal. 8,9 Carnitine is a micronutrient used by the body to transport long chain fatty acids to the mitochondria in cells where fatty acids are converted to adenosine triphosphate. The possible protective mechanisms of carnitine include the inhibition of mitochondrial membrane permeability transition, a decrease of oxidative stress, and the prevention of proapoptotic protein expression.…”

Granulocyte Colony-Stimulating Factor A Noninvasive Regeneration Therapy for Treating Atherosclerotic Peripheral Artery Disease

“…21 It is well known that G-CSF contributes to the healing of myocardial infarction, 7 diabetic ulcers of the skin, 22 and ischemic necrosis resulting from doxorubicin extravasation. 23,24 A recent study also demonstrated that intramuscular injection of G-CSF induced angiogenesis through mechanisms independent of EPC mobilization. 25 These findings suggest that other possible mechanisms of G-CSF, such as direct angiogenesis and wound healing, may play a role.…”

Extravasational toxicity of anticancer chemotherapy and its management

“…However, immediate intervention is indicated in case of non-resolving erythema, pain or swelling and presence of large skin defects. Few experimental animal and human studies have reported good results with the use of granulocyte macrophage colony stimulating factor (GM-CSF) in the management of ulcers in anthracycline extravasation 19,[56][57][58][59] .…”