Mechanism of action of 5-fluorouracil (5-FU), which binds to and inhibits the enzyme thymidylate synthase (TS), thereby reducing DNA synthesis and cell proliferation and inducing cell death.
In the largest series to date supporting the efficacy of topical 5-FU in the treatment of superficial BCC, a histologic cure rate of 90% was reported after 3 weeks for 31 superficial lesions treated twice daily for 11 weeks. Although the follow-up time was short, a treatment resistance rate of 10% was observed. Topical 5-FU is much less effective in nodular BCCs, and its use in this setting has had limited success.
In this article we offer an overview of resistance to nonsurgical treatments in NMSC based on a review of case reports and series and research into the possible mechanisms involved. Studies of resistance will contribute to a better understanding of tumor biology and will help to determine how best to combine treatments to improve response rates and reduce adverse effects.
Additional adaptive responses also need to be considered, such as increased expression of the therapeutic target and activation of alternative compensatory signaling pathways. Cross-resistance is another problem, as once treated, tumors can develop resistance to other drugs, as occurs in multidrug resistance. Finally, certain tumors are highly heterogeneous and contain cells with different phenotypic, genetic, and/or epigenetic characteristics, meaning that sensitivity to treatment will vary according to the area of the tumor.
Resistance can be generally classified as intrinsic or acquired. Intrinsic resistance is characterized by the presence of pre-existing factors that influence how the tumor cells will respond to treatment, while acquired resistance develops after the treatment of a priori sensitive tumors. Intrinsic resistance is a complex process related to diverse biochemical and molecular features of the tumor that allow certain cells to avoid death. Acquired resistance, by contrast, can be caused by different factors, including the limited amount of drug or radiation that reaches the tumor, factors in the tumor environment, and possible mutations that arise in tumor cells during treatment.
Diclofenac is a nonsteroidal anti-inflammatory drug that reduces the production of prostaglandins through inhibition of cyclooxygenase 2 (COX-2) (). There is evidence that COX-2 has an important role in the development and progression of NMSC. COX-2 permits the formation of prostaglandin E (PGE), which in turn enhances tumor proliferation, angiogenesis, and inflammation, and inhibits apoptosis. COX-2 inhibition is thought to achieve the opposite effect, but its mechanism of action in skin cancer cells is unknown. Diclofenac 3% in hyaluronic acid 2.5% (Solaraze) is available as a topical gel approved by the FDA and EMA for the treatment of AK. It is applied twice daily for 60 to 90 days. Although there are studies supporting the use of topical diclofenac in AK, and to a lesser extent Bowen disease, there are no data on its effectiveness in the treatment of BCC or invasive SCC.
One study described the case of a patient with severe dihydropyrimidine dehydrogenase (DPD) deficiency who developed severe gastrointestinal and hematological toxicity following treatment with a standard dose of 5-FU for BCC. DPD is the first enzyme involved in the degradation of 5-FU. Approximately 10% of topical 5-FU is absorbed through the skin while over 80% is inactivated in the liver by DPD, explaining why its deficiency causes toxicity. In the case of colorectal cancer, however, patients with low DPD levels respond better to 5-FU, suggesting that DPD alterations and polymorphisms could be one cause of resistance.
In the first of 2 articles, we will review work on possible mechanisms of resistance to the following topical treatments for NMSC: 5-FU, imiquimod, diclofenac, and ingenol mebutate.
The effectiveness of the above treatments, however, is limited by treatment resistance. Tumor cell resistance is defined as an absence of sensitivity to anticancer drugs and it has multiple, complex causes. Resistance is the main reason why anticancer drugs fail and it has an important role in tumor progression and poor prognosis. Although resistance to chemotherapy and radiotherapy has been extensively studied, we are still far from understanding the mechanisms involved. Generally speaking, the first treatment a patient receives destroys the majority of tumor cells, but if the tumor does not respond adequately to this treatment, resistant cancer cells will remain and may even become more aggressive after several treatment cycles.
The mechanisms of action underlying diclofenac resistance in AK are not clear. Considering the similarities between AK and SCC (mutated and overexpression of COX-2), Rodust et al. used 4 cutaneous SCC cell lines as a model to study resistance to diclofenac in AK. Three of the lines were sensitive to the proapoptotic effects associated with diclofenac-induced caspase activation, while the fourth was resistant. Treatment of diclofenac-sensitive cells produced the characteristic proapoptotic effects at the level of the B-cell lymphoma proteins (Bcl-2) and resulted in the increased expression of Bad (proapoptotic) and the decreased expression of myeloid cell leukemia 1 (Mcl-1) and Bcl-w (both antiapoptotic). However, in the resistant line, the lack of COX-2 prior to treatment with diclofenac was already associated with low levels of Mcl- and Bcl-w and high levels of Bad, possibly due to the lack of PEG in the cells. In such a situation, diclofenac would be unable to exert its proapoptotic effects. However, these resistant cells were also seen to contain underexpressed levels of Noxa and Puma, 2 proapoptotic members of the Bcl-2 family, overall, possibly favoring a COX-2-independent antiapoptotic response to diclofenac.
There are many options available for the treatment of different types of nonmelanoma skin cancer (NMSC), including actinic keratosis (AK). This is important as surgery has its limitations and is not always feasible, such as when patients have multiple and/or extensive lesions or lesions in cosmetically sensitive areas. The introduction of chemotherapy drugs in recent years has increased the treatment options available and produced high complete response rates. Nonsurgical procedures have several advantages. In particular, they are noninvasive, offer excellent cosmetic results, and can be combined with other treatments and repeated. Examples of nonsurgical options used to treat NMSC are retinoids, 5 fluorouracil (5-FU), diclofenac, imiquimod, and photodynamic therapy ().
Cai TB, Tang X, Nagorski J, BrauschweigerPG and Wang PG: Synthesis and cytotoxicity of5-fluorouracil/diazeniumdiolate conjugates. Bioorg Med Chem.11:4971–4975. 2003. : :