Regulation of Epidermal Proliferation in Mouse Epidermis by Combination of Difluoromethyl Ornithine (DFMO) and Methylglyoxal Bis(guanylhydrazone) (MGBG)

Jerry L. McCullough, Patwin Peckham, Jeffrey Klein, Gerald D. Weinstein, Jennifer J. Jenkins
1985 Journal of Investigative Dermatology  
Topical methylglyoxal bis(guanylhydrazone) (MGBG) and alpha-difluoromethylornithine (DFMO) individually have been shown to produce partial clinical improvement in psoriasis. In an effort to further enhance therapeutic activity, studies were designed to optimize percutaneous penetraton of DFMO in vitro and to determine the effects of the combination of DFMO and MGBG on DNA synthesis and polyamine levels in hairless mouse skin. MGBG was shown to be more effective than DFMO in inhibiting DNA
more » ... sis in vitro and in vivo. Maximum in vitro percutaneous penetration of DFMO (5%) was obtained in Vehicle N containing 10% Azone (297 !J.g/h/ cm 2 ) . Topical administration of the combination of 5% DFMO and 0.1 o/o MGBG in this vehicle produced a greater inhibition of DNA synthesis and depletion of polyamine levels than either drug individually. The simultaneous topical administration ofDFMO and MGBG, allowing the use of lower concentrations of the more toxic MGBG, may be useful for therapy of psoriasis and other cutaneous disorders associated with abnormalities in polyamine metabolism. Hyperproliferative cutaneous disorders such as psoriasis and many premalignant and malignant lesions are characterized by increased levels of polyamines and their associated biosynthetic e nzymes [1-3 ). The normalization of polyamines by effective therapeutic moda lit ies [1, 4, 5] has provided the rationale for the use of polyamine inhibitors in the therapy of these diseases. Local (topical or intra lesional) metbylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase (SAMDC) (Fig 1) produces beneficial therapeutic effects in psoriasis [6) and cutaneous malignancies (7), although in psoriasis topical delivery of 10% MGBG produces an unacceptable level of irritation. The topical delivery of alpha-difluoromethylornithine (DFMO) (10 % in a cream base), an irreversible inhibitor of ornithine decarboxylase (Fig 1) , has marginal therapeutic activity in psoriasis [8] . The therapeutic delivery in more effective vehicles has not been explored. Ma nuscript Abbreviations: DFMO: alpha-dilluoromethylornithine MGBG: methylglyoxal bis(guanylhydrazone) ODC: orni thine decarboxylase SA MDC: S-adenosylmethionine decarboxylase TPA: 12-0-tetradecanoyl-phorbol-13-acetate DFMO in combination with MGBG has been shown to have a therapeutic synergism in both experimental tumor models as well as in human malignancies [9, 10] . Effective topical delivery of this combination may be therapeutically useful in proliferative disorders of the skin. The objectives of this study were (1) to quantitate the dose dependence of the combination of DFMO and MGBG on inhibition of DNA synthesis in 12-0-tetradecanoyl-phorbol-13acetate (TP A)-treated hyperproliferative mouse epidermis in vitro; and (2) to optimize the vehicle for topical delivery of DFMO in vitro and study the effects of topical DFMO and MGBG on DNA synthesis and cutaneous polyamine levels in mouse epidermis in vivo . MATERIALS AND METHODS MGBG was obtained from Aldrich Chemical Co., Milwaukee, Wisconsin; Vehicle N (alcohol 47.5 %, water, laureth-4, isopropyl alcohol 4%, propylene glycol) from Neutrogena Corp.,
doi:10.1111/1523-1747.ep12277319 pmid:3934288 fatcat:ojvrssdpqfc5pnnfsbl7o2fycm