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In addition to procedural interventions, and often in combination with these, antimetabolite and antimitotic drugs can be used to treat hypertrophic scars and keloids while also mitigating their likelihood of recurrence. Such drugs can be administered topically, intralesionally, or orally. Intralesional 5-fluorouracil, a pyrimidine analogue with antimetabolite activity that inhibits fibroblast proliferation, is the most common antimetabolite agent for thickened scars. Other options include oral methotrexate, an antimetabolite (antifolate) that prevents reduction of folate to its active form by inhibiting dihydrofolate reductase; intralesional bleomycin, a cytotoxic antibiotic derived from Streptomyces verticellus that has been shown to inhibit collagen synthesis and induce apoptosis; oral colchicine, an antimitotic agent believed to interfere with cell division through its disruptive action on the mitotic spindle, whereby it manifests a specific and dose-dependent inhibitory effect on collagen synthesis and fibroblast proliferation; and topical mitomycin C, a cytotoxic antineoplastic antibiotic produced by Streptomyces caespitosus, with antiproliferative effects on fibroblasts through DNA synthesis inhibition. Notably, virtually all of these scar reduction treatments, while evidence-based, are off-label indications for these drugs.


Hypertrophic scars and keloids are fibrotic lesions resulting from abnormal wound healing and often associated with itching, pain, and redness. Histologically, keloids are composed of increased disorganized, large, thick collagen bundles. The ratio of type I collagen to type III collagen is also elevated compared to normal scars. Both hypertrophic scars and keloids are shown to be associated with increased and persistent activation of fibroblasts, leading to the excessive collagen production compared to normal-healing wounds. Other abnormalities detected in hypertrophic scars and keloids include an increase in water, calcium, fibronectin, collagen type VI, and transforming growth factor (TGF)-[beta]1; certain enzymes such as proline hydroxylase and galactosylhydroxylysyl glucosyltransferase, and cross-linking in the collagen; a decrease in polypeptides of protocollagen as a result of an increase in degradation; and variable concentrations of collagenase and collagen I and III.1

Given that keloid scars have been shown to have increased proliferation similar to many cancers and tumors, many antitumor agents that interfere with cell proliferation have been investigated for their utility for therapeutic benefit. In this chapter, we review the various injectable, topical, and systemic antiproliferative agents used for the treatment of keloids and hypertrophic scars.

Among antimetabolites, the most studied for hypertrophic scars and keloids is 5-fluorouracil. Other antitumor agents also have been reported as experimental and clinical therapies for scars. These include methotrexate, which inhibits the use of a metabolite involved in normal cell metabolism; antimitotic agents such as colchicine; and DNA synthesis inhibitors such as bleomycin and mitomycin C.


History and Mechanism of Action

Perhaps the most well-researched antimetabolite for the treatment of hypertrophic scars and keloids is 5-fluorouracil (5-FU). 5-FU is a pyrimidine analogue with antimetabolite activity that inhibits fibroblast proliferation (Table 11-1). Research demonstrates an inhibitory effect on human ...

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