The uses of systemic chemotherapeutic agents in psoriasis

McDonald, Charles J.

doi:10.1016/0163-7258(81)90008-5

Cited by 22 publications

(8 citation statements)

References 128 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Overall, evaluation of hydroxyurea is difficult because various investigators have used different doses for varying periods and evaluated their patients by different criteria. Although the drug does not appear to improve significantly the natural course of psoriasis, 74 McDonald 81 found that 20–30% of treated patients experience a long‐term remission of their disease. Maximum effects of hydroxyurea occur 4–8 weeks after the start of treatment 72,82 and in pustular psoriasis an earlier response is possible 72 …”

Section: Psoriasismentioning

confidence: 99%

Traditional therapies: glucocorticoids, azathioprine, methotrexate, hydroxyurea

Belgi

Friedmann

2002

Clinical and Experimental Dermatology

View full text Add to dashboard Cite

The 'old favourites' used for treatment of inflammatory diseases, and hence, the original immunomodulators, include the glucocorticoids, azathioprine, methotrexate and hydroxyurea. Glucocorticoids are still one of the most effective anti-inflammatory agents because they work on several different intracellular processes and hence, block many components that contribute to inflammatory and immune responses. They bind to intracellular glucocorticoid receptors which transport them into the nucleus. Here the receptor/steroid complex may bind to many genes that interact with transcription factors including NFkappaB and AP-1, to inhibit their activation, thereby preventing activation of many genes encoding immune effector and pro-inflammatory cytokines. Also, protein kinases involved in intracellular signalling, are directly activated resulting in phosphorylation of various targets of which Annexin (AXA)-1 is critical in inhibiting biosynthesis of both purines and DNA. This results in reduced proliferation of B and T lymphocytes, reduced immune effector mechanisms and reduced recruitment of mononuclear cells including monocytes into sites of immune inflammation. Methotrexate also blocks DNA synthesis and hence cellular proliferation but also induces release of adenosine. This inhibits chemotaxis of polymorph neutrophils and release of critical cytokines such as TNF-alpha and Interleukins 6 and 8. Hydroxyurea also inhibits DNA synthesis with inhibitory effects on proliferation of lymphocytes and possibly kerationcytes. Even though many new agents with much greater selectivity are coming through into clinical use, this group of old agents still have an absolutely central position in the therapeutic armamentarium. Their value lies in the fact that they are not 'clean' drugs with narrow effects but they inhibit a wide range of mechanisms involved in immune and inflammatory processes.

show abstract

Section: Psoriasismentioning

confidence: 99%

Traditional therapies: glucocorticoids, azathioprine, methotrexate, hydroxyurea

Belgi

Friedmann

2002

Clinical and Experimental Dermatology

View full text Add to dashboard Cite

show abstract

“…Hydroxyurea has been used clinically in the treatment of a wide range of solid tumors as well as acute and chronic leukemia (Engstrom et a/. , 1984;Bolin et al, 1982), in the treatment of polycythemia Vera (Donovan et al, 1984), in controlling the proliferation of psoriasis (McDonald, 1981), and as a radiation potentiator (Piver et al, 1983). The drug has also been very useful as a selective agent in tissue culture to isolate drug-resistant cell lines altered in ribonucleotide reductase activity (Wright, 1983(Wright, , 1987McClarty et al, 1987).…”

Section: ?mentioning

confidence: 99%

Molecular and cellular characterization of drug resistant hamster cell lines with alterations in ribonucleotide reductase

Tagger

Wright

1988

Intl Journal of Cancer

View full text Add to dashboard Cite

Ribonucleotide reductase consists of 2 protein components frequently called M1 and M2. Hydroxyurea specifically inhibits DNA synthesis by interacting with the M2 protein and destroying a unique tyrosyl-free radical. We have carried out a molecular and cellular characterization of 2 Chinese hamster ovary cell lines exhibiting either low (HN(R)-AT) or relatively high (H(R)-R2T) resistance to the cytotoxic effects of hydroxyurea. Both drug-resistant lines have an increased level of ribonucleotide reductase activity. EPR measurements for tyrosyl-free radical content and studies with M1-specific antibodies indicated that the elevation in enzyme activity was entirely due to an increase in the M2 component. Studies with M1 cDNA showed that both drug-resistant cell lines contained a wild-type level of M1 mRNA and a wild-type M1 gene copy number. Studies with M2 cDNA indicated that the 2 drug-resistant lines possessed elevated levels of M2 message that could explain the observed increase in M2 component. The elevation of M2 mRNA in the most resistant line, H(R)-R2T, was due to an increase in M2 gene copy number. The low resistant cell line, HN(R)-AT, exhibited a wild-type M2 gene copy number, indicating that the increase in M2 gene message occurred through a process other than gene amplification. Enzyme kinetic studies with partially purified preparations from both drug resistant lines showed reduced sensitivity to hydroxyurea and to the negative allosteric effector, dATP. In addition to hydroxyurea, H(R)-R2T cells were also resistant to several other drugs whose site of action is the M2 component. Furthermore, H(R)-R2T cells were not cross-resistant to colchicine or puromycin, suggesting that hydroxyurea-resistant cells do not share the multi-drug resistance phenotype, which is frequently associated with cross-resistance to these drugs.

show abstract

“…

In uninvolved epidermis from nine psoriatic subjects, the mean phospholipase A2 activity was significantly greater (P < 001) than in nine controls. The increased activity ofthis enzyme could lead to an increase in the concentration of free arachidonic acid which, in turn, could lead to increased concentrations of inflammatory mediators.Psoriasis is a disease characterized by epidermal proliferation and dermal inflammation (for review see McDonald, 1981). The rate limiting factor in the production of inflammatory eicosanoidsf is the concentration of free arachidonic acid (Flower, 1981) and this is very low in normal tissue (Lands, 1979).

…”

mentioning

confidence: 99%

“…Psoriasis is a disease characterized by epidermal proliferation and dermal inflammation (for review see McDonald, 1981). The rate limiting factor in the production of inflammatory eicosanoidsf is the concentration of free arachidonic acid (Flower, 1981) and this is very low in normal tissue (Lands, 1979).…”

mentioning

confidence: 99%