mitoguazone and Psoriasis

Because of its severe side effects, initial clinical trials of the antineoplastic compound mitoguazone (Methyl-GAG, M-G) were ceased in the middle of 1960s. One decade later pharmacokinetically guided dose schedules as well as new experimental data on the antiproliferative mechanism of action stimulated new clinical studies. First results indicated that M-G had single-agent activity against various tumors such as acute leukemia and malignant lymphoma connected with acceptable tolerance. M-G seems to be effective especially in combination with other antineoplastic drugs. Its final evaluation may be reserved to further randomized trials. Recently, the psoriasis vulgaris is expected to be an additional field of the application of M-G. In this minireview data on synthesis, preclinical pharmacology, pharmacokinetics, biochemical effects and toxicology of M-G are given. Furthermore, clinical findings on M-G concerning its pharmacokinetic behaviour, antitumor and antipsoriatic activities are described.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Humans; Lethal Dose 50; Mitoguazone; Neoplasms; Psoriasis

Because of its severe side effects, initial clinical trials of the antineoplastic compound mitoguazone (Methyl-GAG, M-G) were ceased in the middle of 1960s. One decade later pharmacokinetically guided dose schedules as well as new experimental data on the antiproliferative mechanism of action stimulated new clinical studies. First results indicated that M-G had single-agent activity against various tumors such as acute leukemia and malignant lymphoma connected with acceptable tolerance. M-G seems to be effective especially in combination with other antineoplastic drugs. Its final evaluation may be reserved to further randomized trials. Recently, the psoriasis vulgaris is expected to be an additional field of the application of M-G. In this minireview data on synthesis, preclinical pharmacology, pharmacokinetics, biochemical effects and toxicology of M-G are given. Furthermore, clinical findings on M-G concerning its pharmacokinetic behaviour, antitumor and antipsoriatic activities are described.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Humans; Lethal Dose 50; Mitoguazone; Neoplasms; Psoriasis

In this national, multicenter cooperative study, a standardized drug screening program was designed and evaluated to test the clinical effectiveness of 30 topically applied chemotherapeutic drugs to psoriasis. Appropriate concentrations and vehicles for topical administration were selected with regard to clinical testing consisted of a double-blind application of test agents to psoriatic plaques under occlusion daily for up to nine days. Drugs known to be topically active in psoriasis, eg, thiotepa, fluorouracil, and betamethasone valerate, were easily detected in the clinical protocol, confirming the validity of this topical drug screening program. Seven drugs produced substantial clinical improvement with evidence of clearing; nine drugs produced slight improvement; 14 drugs had no effect. No systemic toxid reactions occurred. This screen should be useful to test other potential antipsoriatic drugs and to evaluate potential animal model screens for their predictive values with the same drugs.

Topics: Adult; Animals; Clinical Trials as Topic; Cycloheximide; Dermatologic Agents; Double-Blind Method; Drug Evaluation, Preclinical; Emetine; Fluorouracil; Humans; Mitoguazone; Psoriasis; Pyrimethamine; Rabbits; Skin; Thiotepa

We describe the effect of two polyamine antimetabolites on polyamine and macromolecule synthesis of cultured human keratinocytes obtained by suction blisters from normal skin and the uninvolved skin of psoriatic patients. The concentrations of spermidine and spermine steadily increased during the culture of normal keratinocytes in vitro, whereas the putrescine concentration showed only a transient rise at the beginning of the active growth phase. Treatment with difluoromethylornithine decreased the concentrations of putrescine and spermidine in both normal and uninvolved psoriatic keratinocytes, but had no effect on either DNA or protein synthesis. Methylglyoxal bis(guanylhydrazone) marginally decreased the levels of spermidine and spermine and significantly inhibited the DNA and protein synthetic activities. Pretreatment of uninvolved psoriatic keratinocytes with difluoromethylornithine enhanced the accumulation of methylglyoxal bis(guanylhydrazone), resulting in a profound inhibition of cellular macromolecule synthesis. This synergistic effect was not seen in normal keratinocytes. Thus, although no statistically significant difference was observed between the cells derived from normal and uninvolved psoriatic epidermis, the psoriatic keratinocytes appeared to be more sensitive to the action of polyamine antimetabolites. The inhibition of DNA and protein synthesis by methylglyoxal bis(guanylhydrazone) was prevented by concomitant treatment with spermidine.

Topics: Antimetabolites; Cell Division; Cells, Cultured; DNA; Eflornithine; Guanidines; Humans; Keratins; Mitoguazone; Ornithine; Protein Biosynthesis; Psoriasis; Putrescine; Skin; Spermidine; Spermine

Topical methylglyoxal bis(guanylhydrazone) (MGBG) previously has been shown to produce partial clinical improvement in psoriasis. To enhance therapeutic activity, studies were undertaken to optimize MGBG percutaneous penetration in vitro and to study biochemical changes related to epidermal proliferation in vivo. MGBG penetration in saline, Vehicle N, decylmethylsulfoxide, and N-methylpyrrolidone was determined in normal human skin in vitro. Maximum penetration was obtained with 10% MGBG in Vehicle N (3 micrograms/h/cm2). Both topical and systemic MGBG resulted in increased levels of S-adenosyl-L-methionine decarboxylase, suggesting an extended half-life as a consequence of MGBG binding. Topical treatment with 10% MGBG in Vehicle N also resulted in decreased epidermal polyamine levels. The changes in polyamine metabolism were also associated with inhibition of epidermal DNA synthesis. These studies suggest that this topical MGBG formulation may be a candidate for use in the treatment of psoriasis and other hyperproliferative cutaneous diseases associated with increased polyamine synthesis.

Topics: Administration, Topical; Animals; DNA; Eflornithine; Guanidines; In Vitro Techniques; Mice; Mice, Hairless; Mitoguazone; Ornithine; Polyamines; Psoriasis; Skin; Skin Absorption

Topics: Carboxy-Lyases; Dose-Response Relationship, Drug; Eflornithine; Guanidines; Humans; Injections, Intradermal; Mitoguazone; Ornithine; Ornithine Decarboxylase Inhibitors; Polyamines; Psoriasis; Putrescine; Skin; Spermidine; Spermine