Cutaneous Carcinogenesis Related to Dermatologic Therapy

Introduction

Any systemic treatment is associated with the risk of systemic side effects. The prudent physician must use caution when prescribing such therapy and is obliged to be alert that the therapy does not pose an additional significant risk to the patient. The clinician must weigh the benefits of the treatment or medication against its potential adverse effects by carefully assessing drug associations and toxicities. Regardless of the care taken, adverse effects may never completely be avoided given the imperfect nature of medical risk reduction and the unpredictability of the human body. It is important to minimize the untoward consequences of the pharmacotherapy and phototherapy used that may increase cutaneous carcinogenesis.

Potential mechanisms of drug-related carcinogenesis

Skin cancer represents a breach in the defense mechanisms necessary to ensure that proliferation and differentiation of skin cells occur within bounds. The disruptions of these mechanisms, environmental or programmed, may take the form of new promoters that invite unregulated cell growth or the loss of suppressors to prevent such growth, creating cells which lose their original confinement, invade and disrupt surrounding tissues.

Mutations of the p53 tumor suppressor gene are among the most frequent abnormalities found in the genome of human cancers. The p53 gene has a regulatory role in activating DNA repair, holding the cell cycle at the G1/S phase, and initiating apoptosis, all of which prevent mutation and subsequent carcinogenesis. In the functional cell, p53 products are continuously degraded and kept at low levels. However, p53 expression becomes activated in response to a number of stress types, such as ultraviolet light (UV), ionizing radiation (IR), or chemically induced DNA damage. There are three cellular pathways that provoke the functioning p53 system. IR induces the first pathway by activating two protein kinases, ataxia telangiectasia-mutated (ATM) and CHK2 checkpoint homolog. The second pathway results from abnormal growth signals, particularly from the expression of the proteins RAS and Bcl-2. The third path is prompted by ultraviolet light, chemotherapeutic agents and kinase inhibitors, and is not dependent on Chk2, p14 or ATM . Data show that p53 mutations are present in approximately 56% of human basal cell carcinomas (BCC), 40–60% of squamous cell carcinomas (SCC), and 10% of malignant melanomas (MM).

The hedgehog signaling pathway is also vital to proper cellular differentiation. Regulatory errors or mutations in the hedgehog pathway are associated with carcinogenesis as well as prenatal defects. Central to this cascade lies a tumor suppressor gene called patched (Ptc). In the normally functioning cell, Ptc prevents a molecule called smoothened (Smo) from initiating growth signals. When hedgehog (Hh) proteins bind to the Ptc–Smo complex, Smo separates from Ptc, enabling it to activate a transcription factor named Gli. Gli then migrates into the nucleus, where it influences a variety of target genes. It has been found that Hh augments the cell's capacity for long-term growth. Misregulated Hh may also induce the Bcl-2 pathway, creating anti-apoptotic products that promote that aberrant growth and eventually tumorigenesis. The hedgehog pathway is especially implicated in the formation of BCC, both genetic and sporadic. Recent data demonstrate that the expression of Gli1 in basal cells is likely to induce BCC formation. There is also evidence that the Ptc gene may be mutated in cutaneous SCC.

Thus, it is helpful to understand the molecular basis for skin cancer as a background for the comprehension of drug and physical treatment-induced tumorigenesis, since all of the therapies discussed here are thought to exert their potentially harmful effects at the molecular level.

Therapies associated with increased skin cancer risk

( Table 32.1 )