Mygophenolig Acid : Antiviral and Antitumor Properties

Williams, Robert H.; Lively, David H.; DeLong, Donald C.; Cline, J. C.; Sweeney, Martin J.; Poore, Gerald A.; Larsen, Stephen H.

doi:10.7164/antibiotics.21.463

Cited by 121 publications

(46 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Specific inhibitors of IMP dehydrogenase, e.g., MPA, have been of therapeutic importance as drugs with antiviral and antitumor activities (53) and have been discussed as potential chemotherapeutic agents for protozoan infections (5). Resistance to MPA in some kinetoplastid protozoans involves interesting mechanisms of chromosomal and extrachromosomal IMP dehydrogenase gene amplification (56,57).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of a cloned IMP dehydrogenase gene of Candida albicans confers resistance to the specific inhibitor mycophenolic acid

1997

View full text Add to dashboard Cite

An IMP dehydrogenase gene was isolated from Candida albicans on a ϳ2.9-kb XbaI genomic DNA fragment. The putative Candida IMP dehydrogenase gene (IMH3) encodes a protein of 521 amino acids with extensive sequence similarity to the IMP dehydrogenases of Saccharomyces cerevisiae and various other organisms. Like the S. cerevisiae IMH3 sequence characterized in the genome sequencing project, the open reading frame of the C. albicans IMH3 gene is interrupted by a small intron (248 bp) with typical exon-intron boundaries and a consensus S. cerevisiae branchpoint sequence. IMP dehydrogenase mRNAs are detected in both the yeast and hyphal forms of C. albicans as judged by Northern hybridization. Growth of wild-type (sensitive) C. albicans cells is inhibited at 1 g of mycophenolic acid (MPA), a specific inhibitor of IMP dehydrogenases, per ml, whereas transformants hosting a plasmid with the IMH3 gene are resistant to MPA levels of up to at least 40 g/ml. The resistance of cells to MPA is gene dosage dependent and suggests that IMH3 can be used as a dominant selection marker in C. albicans.IMP dehydrogenase (EC 1.1.1.205) is the key enzyme in the de novo biosynthesis of GMP, catalyzing the NAD-dependent oxidation of IMP to XMP. This conversion of IMP to XMP is the rate-limiting step in the biosynthetic pathway of guanine nucleotides, at least in mammals (26). While genes encoding IMP dehydrogenases have been isolated from archaea (11), protozoa (5, 54, 55), bacteria (2,3,16,31,36,47,49), plants (12), invertebrates (46), and mammals (10, 13, 39, 50), the only fungal sequences known are those encoding the putative IMP dehydrogenase genes sequenced in the Saccharomyces cerevisiae genome project (14,27,28). The polymorphic fungus Candida albicans is an opportunistic pathogen in immunocompromised individuals, causing oral and vaginal candidiasis as well as disseminated infections in neutropenic patients. Genetic manipulations of this diploid microorganism have been hampered by the apparent absence of a haploid phase and the dependence of marker systems on the spontaneous occurrence of auxotrophic mutants. Thus, the identification of the IMH3 gene in C. albicans suggested to us that mycophenolic acid (MPA), a specific inhibitor of IMP dehydrogenases, might be used to develop a dominant selectable marker system in Candida. In several other organisms, it has been shown that amplification of an IMP dehydrogenase gene can confer MPA resistance in a gene-dosage-dependent manner by overexpression of the enzyme (9,20,23,25,54). We report the cloning and sequencing of a DNA fragment of C. albicans with a coding region for a protein with high amino acid similarity and identity to known IMP dehydrogenases. Transformation of C.albicans by using a multicopy plasmid vector yielded transformants resistant to the specific IMP dehydrogenase inhibitor MPA. Culturing of transformant cells in the presence of MPA stabilized replicative plasmids, suggesting the feasibility of using IMH3 as a dominant selection marker for genetic studies in C. alb...

show abstract

Section: Discussionmentioning

confidence: 99%

Overexpression of a cloned IMP dehydrogenase gene of Candida albicans confers resistance to the specific inhibitor mycophenolic acid

1997

View full text Add to dashboard Cite

show abstract

“…IMPDH inhibitors are expected to mainly affect viral RNA and/or DNA synthesis when there is an increased need for synthesis, as in the case of virus-infected cells. IMPDH inhibition decreases levels of intracellular guanine nucleotide pools required for adequate RNA and DNA synthesis; therefore, inhibition of IMPDH with MPA has been shown to have antiproliferative (7), immunosuppressive (42), antimicrobial (43), antiviral (63,70), and antiparasitic (3,29) effects. Currently, MPA is used clinically to prevent rejection of transplanted kidneys and hearts in combination with steroids and cyclosporine A (2,33,66).…”

mentioning

confidence: 99%

Inhibition of Reovirus by Mycophenolic Acid Is Associated with the M1 Genome Segment

Hermann

Coombs

2004

J Virol

View full text Add to dashboard Cite

Mycophenolic acid (MPA), an inhibitor of IMP dehydrogenase, inhibits reovirus replication and viral RNA and protein production. In mouse L929 cells, antiviral effects were greatest at 30 g of MPA/ml. At this dosage, MPA inhibited replication of reovirus strain T3D more than 1,000-fold and inhibited replication of reovirus strain T1L nearly 100-fold, compared to non-drug-treated controls. Genetic reassortant analysis indicated the primary determinant of strain-specific differences in sensitivity to MPA mapped to the viral M1 genome segment, which encodes the minor core protein 2. MPA also inhibited replication of both strains of reovirus in a variety of other cell lines, including Vero monkey kidney and U373 human astrocytoma cells. Addition of exogenous guanosine to MPA-treated reovirus-infected cells restored viral replicative capacity to nearly normal levels. These results suggest the 2 protein is involved in the uptake and processing of GTP in viral transcription in infected cells and strengthens the evidence that the 2 protein can function as an NTPase and is likely a transcriptase cofactor.

show abstract

“…Thus, Ehrlich tumor cells may lose their viability when incubated with free fatty acids and mono glycerides from three strains of hemolytic streptococci or with diphosphatidyl glycerols from two strains of the streptococci (Black more and C203U). There are many studies indicating that free fatty acids and their esters are highly cytotoxic to tumor cells, and these cytotoxic lipids are the factors responsible for the antitumor activity of fungi or mammalian cells (3)(4)(5)(6)(7)(8). Therefore, it is likely that the cytotoxic lipids, such as free fatty acids or monoglycerides, are involved in the antitumor activity of the group A streptococci.…”

Section: Discussionmentioning

confidence: 99%

“…Many studies have indicated that the lipids extracted from fungi or mammalian cells are cytotoxic to tumor cells (3)(4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

Effect of streptococcal lipids on Ehrlich ascites tumor cells.

Kigoshi

Kitajima

1981

Jpn.J.Pharmacol

View full text Add to dashboard Cite

Abstract-The lipids extracted from group A hemolytic streptococci (strain Su, Blackmore and C203U) were examined for their antitumor effect against Ehrlich ascites carcinoma in mice. Total lipids were extracted from strep tococcal cells according to the method of Folch et al, and separated into 9 lipid fractions by thin-layer chromatography, using various solvent systems.Three fractions were compound lipids (diphosphatidyl glycerols, monoglucosyl diglycerides and diglucosyl diglycerides), and the remaining 6 fractions were neutral lipids such as free fatty acids, glycerides, sterols and sterol esters.For biological testing, the lipid fractions suspended in physiological saline containing Tween 20 (0.02%) were incubated with Ehrlich tumor cells at 37°C for 90 min, and the cell mixture was given intraperitoneally into mice thereafter. Among 9 lipid fractions, free fatty acids and monoglycerides from the streptococci examined were highly active in suppressing the development of ascites carcinoma in mice. Dipho sphatidyl glycerols from two strains of streptococci (Blackmore and C203U) were also effective in suppressing the tumor growth in mice. However, the other lipid fractions had little effect on the tumor growth.

show abstract

Mygophenolig Acid : Antiviral and Antitumor Properties

Cited by 121 publications

References 5 publications

Overexpression of a cloned IMP dehydrogenase gene of Candida albicans confers resistance to the specific inhibitor mycophenolic acid

Overexpression of a cloned IMP dehydrogenase gene of Candida albicans confers resistance to the specific inhibitor mycophenolic acid

Inhibition of Reovirus by Mycophenolic Acid Is Associated with the M1 Genome Segment

Effect of streptococcal lipids on Ehrlich ascites tumor cells.

Contact Info

Product

Resources

About