Eflornithine Treatment of Refractory Pneumocystis carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome

Paulson, Yana J.; Gilman, Thomas M.; Heseltine, Peter N. R.; Sharma, Om P.; Boylen, C. Thomas

doi:10.1378/chest.101.1.67

Chest

1992

DOI: 10.1378/chest.101.1.67

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Eflornithine Treatment of Refractory Pneumocystis carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome

Yana J. Paulson

Thomas M. Gilman

Peter N. R. Heseltine

et al.

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Cited by 26 publications

(17 citation statements)

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“…Eflornithine (difluoromethylornithine, DFMO, Ornidyl) is among the alternative drugs for PCP treatment. Both clinical (9,10,13,16,17) and animal (4, 5) data indicate that eflornithine is active against PCP. However, the efficacy of eflornithine is less than those of the standard drugs and some of the other alternative treatments (18).…”

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Ornithine decarboxylase in Pneumocystis carinii and implications for therapy

Sarić

Clarkson

1994

Antimicrob Agents Chemother

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Pneumocystis carinii pneumonia (PCP) can be treated with eflornithine (difluoromethylornithine, DFMO, Ornidyl), a competitive irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme for polyamine biosynthesis. Because ODC has been reported to be absent from P. carinii, it has been assumed that eflornithine affects P. carinii only indirectly, by affecting host polyamine biosynthesis. If this is true, then improvements in the selectivity of antipolyamine therapy for PCP would be limited. Since the presence of ODC in P. carinii is an important issue, a new search for this enzyme was made. Not only were initial assays negative, but P. carinii extract reduced the background catalytic action of pyridoxal-5'-phosphate, the coenzyme required by the enzyme. This suggested the presence of an inhibitor, which was further supported by the observation that a P. carinii extract could suppress a source of known ODC activity. The inhibitory activity could be removed by a desalting column or by dialysis, allowing detection of P. carinii ODC. Indirect evidence indicates that the inhibition is only apparent and is caused by unlabeled ornithine in the extract ofP. carinii which interferes with the radiolabel-based assay system. P. carinii and host ODCs respond differently to changes in pH. P. carinii ODC is much less susceptible to inhibition by eflornithine than host ODC. The presence of ODC in P. carinii suggests that P. carinii ODC is the target of efiornithine and that P. carinii ODC may have sufficiently specific properties that inhibitors with improved selectivity against P. carinii ODC could be identified.Pneumocystis carinii is an opportunistic eukaryotic microorganism that causes a severe pneumonia (P. carinii pneumonia [PCP]) in immunocompromised individuals, and PCP is the most frequently diagnosed opportunistic infection associated with AIDS (11). Notwithstanding the discovery of several alternative drugs, co-trimoxazole and pentamidine have remained the drugs of choice for both prophylaxis and therapy in spite of their toxicity and lack of perfect efficacy (18). Eflornithine (difluoromethylornithine, DFMO, Ornidyl) is among the alternative drugs for PCP treatment. Both clinical (9,10,13,16,17) and animal (4, 5) data indicate that eflornithine is active against PCP. However, the efficacy of eflornithine is less than those of the standard drugs and some of the other alternative treatments (18).Eflornithine was designed to inhibit ornithine decarboxylase (ODC), a critical enzyme in the biosynthesis of polyamines, which are small compounds required by all cells (14). Eflornithine is a suicide enzyme inhibitor in that it is ineffective until decarboxylated by ODC, which leads to the covalent binding of the decarboxylated eflornithine to the active site of the enzyme; this specifically and irreversibly inhibits ODC (1). In tissue culture studies in which P. carinii was grown on mammalian feeder-layer cells, eflornithine was shown to exert its action through interference with polyamine metabolism, at least to t...

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Ornithine decarboxylase in Pneumocystis carinii and implications for therapy

Sarić

Clarkson

1994

Antimicrob Agents Chemother

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“…However, TMP-SMZ may cause adverse effects, such as fever and rash (37), and TMP-SMZ-resistant Pneumocystis strains have emerged (28), probably due to point mutations at codon 55 or 57 of the DHPS gene of Pneumocystis jirovecii (18,41). Clindamycin-primaquine, atovaquone, and pentamidine are alternative therapies for PCP; however, they are also associated with the issues of side effects.Another potential target for treatment of PCP is polyamine synthesis (8,9,14,32,36,39). Polyamines are essential organic compounds for cell growth (20,26).…”

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confidence: 99%

“…It also has activity against Plasmodium falciparum (30), Giardia lamblia (13), Eimeria tenella (16), and Trichomonas vaginalis (47). DFMO has also been used to treat PCP in humans, with success rates ranging from 33 to 57% (14,32,36,38,39). This partial success suggests that targeting polyamine synthesis alone is not sufficient for treatment of PCP.…”

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Polyamine Transport as a Target for Treatment ofPneumocystisPneumonia

Liao

Phanstiel

Lasbury

et al. 2009

Antimicrob Agents Chemother

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Polyamine levels are greatly increased in alveolar macrophages (AMs) during Pneumocystis pneumonia (PCP), leading to increased production of H 2 O 2 , which causes AMs to undergo apoptosis. One of the mechanisms by which polyamine levels in AMs are elevated is enhanced uptake of exogenous polyamines. In this study, the possibility of targeting polyamine uptake as a treatment for PCP was examined. Pneumocystis pneumonia (PCP) is the leading opportunistic disease in AIDS patients. PCP can be life threatening, as it may cause extensive pulmonary injury, impaired gas exchange, and respiratory failure. The first-line drug for both prophylaxis and treatment of PCP is a combination of trimethoprim and sulfamethoxazole (TMP-SMZ) (40). TMP and SMZ inhibit dihydrofolate reductase and dihydropteroate synthase (DHPS), respectively (18). However, TMP-SMZ may cause adverse effects, such as fever and rash (37), and TMP-SMZ-resistant Pneumocystis strains have emerged (28), probably due to point mutations at codon 55 or 57 of the DHPS gene of Pneumocystis jirovecii (18,41). Clindamycin-primaquine, atovaquone, and pentamidine are alternative therapies for PCP; however, they are also associated with the issues of side effects.Another potential target for treatment of PCP is polyamine synthesis (8,9,14,32,36,39). Polyamines are essential organic compounds for cell growth (20,26). The rate-limiting enzyme of polyamine synthesis is ornithine decarboxylase (ODC), which is usually increased in proliferating cells. ␣-Difluoromethylornithine (DFMO, also known as eflornithine) is a potent ODC inhibitor with low cytotoxicity. DFMO was first developed as an anticancer drug and was shown to be effective for treatment of trypanosomiasis (2,29). It also has activity against Plasmodium falciparum (30), Giardia lamblia (13), Eimeria tenella (16), and Trichomonas vaginalis (47). DFMO has also been used to treat PCP in humans, with success rates ranging from 33 to 57% (14,32,36,38,39). This partial success suggests that targeting polyamine synthesis alone is not sufficient for treatment of PCP.Our recent studies revealed that polyamine levels in alveolar macrophages (AMs) are greatly increased during PCP, resulting in an elevated apoptosis rate and impaired Pneumocystis clearance activity by AMs (23). We also found that the increased intracellular polyamine levels were at least partially due to increased uptake of exogenous polyamines (25). Based on these findings, we hypothesized that polyamine uptake can be a target for treatment of PCP and tested five potential polyamine transport (PAT) inhibitors. Results showed that compound 44-Ant-44 was effective against PCP in a rat model.

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“…This drug is currently approved for treatment of human African sleeping sickness (4) and has been used as an investigational drug for cancer chemotherapy and for treatment of Pneumocystis carinii pneumonia (PCP), the most common opportunistic infection associated with AIDS. DFMO is effective against PCP, in an animal model (5) and in patients (6). Although clinical trials showed this drug to be less effective than drugs already approved, it was also less toxic (7).…”

mentioning

confidence: 99%

Pneumocystis carinii Polyamine Catabolism

Merali

1999

Journal of Biological Chemistry

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DL-␣-Difluoromethylornithine (DFMO) causes polyamines of the AIDS-associated opportunistic pathogenPneumocystis carinii to diminish 15 times more rapidly than mammalian host cells. The proposed mechanism was that, unlike mammalian cells, P. carinii is unable to regulate polyamine catabolism when synthesis is blocked. To test this, the responses of the polyamine catabolic enzymes spermidine/spermine acetyltransferase (SSAT) and polyamine oxidase (PAO) were determined using a new high-performance liquid chromatography assay to measure the products of these enzymes. The specific activities in untreated Pneumocystis carinii were 1.78 ؎ 0.5 pmol min ؊1 mg protein ؊1 for SSAT, similar to mammalian cells, and 6.42 ؎ 0.8 pmol min ؊1 mg protein ؊1 for PAO, 19% of that of mammalian cells. DFMO treatment for 12 h caused reductions of only 11 and 4% in SSAT and PAO, respectively, despite polyamine reductions of 94, 96, and 90% for putrescine, spermidine, and spermine, respectively. The P. carinii SSAT K m value of 25 M spermidine is 20% of that of mammalian cells, and the PAO K m value of 14 nM N 1 -acetylspermidine is 0.01% of that of mammalian cells. Acetylated polyamines continue to be lost from P. carinii even when exposed to DFMO. Collectively, these results support the hypothesis that P. carinii is unable to regulate polyamine catabolism.Polyamines are small molecular weight, positively charged compounds that are ubiquitous in all living cells. The most important polyamines are putrescine, spermidine, and spermine. Although much of the evidence is indirect, it is clear that polyamines play many important roles in cell growth and differentiation (1-3). Consequently, inhibition of polyamine synthesis, as well as other means of manipulating polyamine concentrations, has been used as therapeutic approaches for the treatment of cancer and infectious diseases.The most commonly used compound for manipulating polyamine metabolism is difluoromethylornithine (DFMO, 1 eflornithine, Ornidyl ® ). DFMO is an enzyme-activated irreversible inhibitor of ornithine decarboxylase, an enzyme that catalyzes the first step in polyamine synthesis and is rate-limiting. Thus DFMO can completely block de novo polyamine synthesis. This drug is currently approved for treatment of human African sleeping sickness (4) and has been used as an investigational drug for cancer chemotherapy and for treatment of Pneumocystis carinii pneumonia (PCP), the most common opportunistic infection associated with AIDS. DFMO is effective against PCP, in an animal model (5) and in patients (6). Although clinical trials showed this drug to be less effective than drugs already approved, it was also less toxic (7). Animal studies, however, demonstrated that continuous infusion of DFMO greatly enhances the anti-PCP activity as compared with the intermittent dosage obtained by inclusion of the drug in the drinking water (8). The activity of DFMO against PCP demonstrates that polyamine metabolism is a valid therapeutic target for this disease. A better understanding of P....

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Eflornithine Treatment of Refractory Pneumocystis carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome

Cited by 26 publications

References 25 publications

Ornithine decarboxylase in Pneumocystis carinii and implications for therapy

Ornithine decarboxylase in Pneumocystis carinii and implications for therapy

Polyamine Transport as a Target for Treatment ofPneumocystisPneumonia

Pneumocystis carinii Polyamine Catabolism

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