Haptens as drugs: contact allergens are powerful topical immunomodulators

Journal of Drugs in Dermatology, May, 2006 by Aton M. Holzer, Leonard L. Kaplan, William R. Levis

Abstract

For the past 40 years, dermatologists have safely used contact sensitizers such as dinitrochlorobenzene (DNCB), diphenylcyclopropenone (DPCP), and squaric acid dibutylester (SADBE) for the treatment of warts, alopecia areata, and even skin cancers. Most of these studies have utilized these powerful topical immunomodulators in acetone, a volatile solvent that precludes development of contact sensitizers as products. We have overcome these problems and stabilized these topical immunomodulators in a non-volatile, nonirritating GRAS (generally regarded as safe) vehicle. The current review article covers the traditional use of contact sensitizers for a variety of benign and malignant conditions and discusses possible mechanisms in relation to developments in modern molecular immunodermatology.

Introduction

Topical or contact sensitizers--substances that induce allergic contact dermatitis in areas of application--have been used to treat cutaneous disease since 1965, when the alkylating agent triethyleneiminobenzoquinone (TEIB) was found to have utility in the treatment of superficial basal and squamous cell carcinomas. (1) TEIB was abandoned when it was found to have mutagenic properties. (2) Since then, a series of agents have been explored for their therapeutic value as topical sensitizers, including nitrogen mustard, poison ivy, nickel, formalin, primin, and tuberculin jelly, but these have been mostly superseded by the more reliably allergenic and environmentally absent substances dinitrochlorobenzene (DNCB), squaric acid dibutylester (SADBE), and diphenylcyclopropenone (DPCP). (3)

Clinical Utility

DNCB, SADBE, and DPCP have been employed in dermatology clinics to treat a variety of benign and malignant dermatoses, though none has received the imprimatur of the US Food and Drug Administration (FDA). All are contact sensitizers, and the 3 agents, though possessing distinct molecular structures, share some basic structural similarities and appear to share the same mechanism of action. (4)

I. Human Papillomavirus

Contact sensitizers have been reported to show efficacy in the treatment of warts, (5) and are reported to be less painful and scarring than other types of wart treatment. (6) DNCB, DPCP, and SADBE have proven effective at eliminating even refractory, relapsing warts, (7) as well as plane warts, (8) hyperkeratotic tumor-like warts, (9) conjunctival warts, (10) and mucocutaneous genital warts, (11) and show particular utility in treating palmoplantar and periungual warts. (12,13) Localized inflammation and involution of warts has been reported even for untreated warts distant from application of topical sensitizer. (14-16) Remissions have also been reported for condylomata acuminata (17) and vulvar intraepithelial neoplasia. (18)

II. Skin Cancers

Topical sensitizers have also demonstrated success in the eradication of basal and squamous cell carcinomas, (19-21) Bowen's disease, (22) and even metastatic Merkel cell carcinoma; (23) additionally regression and remissions have been seen in cases of malignant melanoma (24) and in-transit melanoma metastases. (25) Indeed, DNCB had first been noted to successfully spur regression of primary cutaneous malignant melanoma lesions in 1973, (26) but DNCB monotherapy has rarely had any effect on metastases. (27-30) Two groups have recently reported success with epifocal application of DNCB following systemic chemotherapy with dacarbazine (DTIC). (31,32) Another approach employing haptens in melanoma is exogenous, in vitro haptenation. David Berd's group has devised M-Vax, a melanoma tumor vaccine employing autologous cancer cells haptenated with dinitrophenyl (DNP) recently approved in France. Phase II clinical trials in Stage III melanoma patients reveal a 44% 5-year overall survival, significantly better than the 20% to 25% 5-year survival rates reported in most studies. (33)

III. Cutaneous T cell Lymphoma (CTCL)

Topical sensitizer therapy has been successfully employed in cutaneous T cell lymphoma; (34-37) topical therapy with the sensitizer and alkylating agent nitrogen mustard mechlorethamine has shown particularly good results, (38,39) but its use has been limited by its carcinogenicity. Responses to topical sensitizers have also been seen to have prognostic significance regarding disease progression in CTCL; Vonderheid's group demonstrated that DNCB test positivity was correlated with a significantly lower likelihood of experiencing disease progression and a better overall prognosis. (40)

IV. Alopecia Areata

Contact sensitizers have shown particular efficacy both as monotherapy (41,42) and in combination with other therapies (43) in the treatment of alopecia areata. A recent open-label clinical trial with DPCP concluded that topical sensitizers are effective and well-tolerated in extensive alopecia areata (AA) and provide prolonged therapeutic benefits. (44) Five factors of prognostic significance have surfaced in several large clinical trials of DPCP and SADBE in AA: type of AA (patchy, ophiasis, diffuse, totalis, universalis), presence of nail changes, duration of AA before treatment, age at onset and association with atopic dermatitis. (45-47) In a comprehensive review, Rokhsar et al found that SADBE and DPCP have a success rate of approximately 50% to 60% in hair regrowth in alopecia areata, but recommend that their use be restricted to more extensive disease (>40% scalp involvement). (4)

V. Other

Contact sensitizers have additionally been reported to show utility in the treatment of chronic nodular prurigo, (48) lichen nitidus, (49) and atopic dermatitis; (50,51) efficacy in the context of atopy raises the question of possible utility of topical sensitizers in asthma. Topical sensitizers further appear to improve joint symptoms and immune status in systemic lupus erythematosus. (52) Topical sensitizers have also shown prognostic utility in predicting the likelihood of rejection of hepatic allografts, (53) and have theoretical potential in prognosis of rejection in other allografts, including renal and bone marrow transplantation. One study at high doses failed to show any utility in assessing immune competence in leukemias, (54) although leukemia-associated disruptions or alterations of cell-mediated immunity have been reported. (55)