Novel Lysine–Spermine Conjugate Inhibits Polyamine Transport and Inhibits Cell Growth When Given with DFMO

Weeks, Reitha S.; Vanderwerf, Scott M.; Carlson, C. Lance; Burns, Mark R.; O’Day, Christine; Cai, Feng; Devens, Bruce H.; Webb, Heather K.

doi:10.1006/excr.2000.5033

Cited by 48 publications

(53 citation statements)

References 33 publications

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“…MQT 1426 was synthesized using an adaptation of the method previously described for the synthesis of L-Lys-spm (ORI 1202). 11,12 The synthesis can be summarized as follows. The 4-nitrophenyl ester of a,‹-Boc-D-lysine was coupled to the free base of spermine in methanol.…”

Section: Drugsmentioning

confidence: 99%

“…Both sources could, in theory, be used to replete cellular polyamine levels in tumor cells undergoing regimens involving DFMO. With the recent availability of a high affinity inhibitor of polyamine transport, 11 we reasoned that combination therapy of SCCs with both DFMO and a polyamine transport inhibitor (PTI) might improve the therapeutic response to DFMO. Combination therapy might also permit the use of lower doses of DFMO than when typically used in therapy or prevention studies (1-3%, orally).…”

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confidence: 99%

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Combination therapy with 2‐difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma

Chen

Weeks

Burns

et al. 2005

Intl Journal of Cancer

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Using a recently developed autochthonous mouse model of squamous cell carcinoma (SCC), a combination therapy targeting polyamine metabolism was evaluated. The therapy combined 2-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), and MQT 1426, a polyamine transport inhibitor. In 1 trial lasting 4 weeks, combination therapy with 0.5% DFMO (orally, in the drinking water) and MQT 1426 (50 mg/kg i.p., bid) was significantly more effective than with either single agent alone when complete tumor response was the endpoint. In the combination group, 72% of SCCs responded completely vs. 21 and 0% for DFMO and MQT 1426, respectively. A second trial involved a 4-week treatment period followed by 6 weeks off-treatment. With apparent cures as an endpoint, combination therapy was again more effective than either agent alone: a 50% apparent cure rate was observed in the combination group vs. 7.7% in the DFMO group. MQT 1426 had no inhibitory effect on SCC ODC activity nor did it enhance the inhibition by DFMO, but SCC polyamine levels declined more rapidly when treated with combination therapy vs. DFMO alone. The apoptotic index in SCCs was transiently increased by combination therapy but not by DFMO alone. Thus, targeting both polyamine biosynthesis and polyamine transport from the tumor microenvironment enhances the efficacy of polyamine-based therapy in this mouse model of SCC. ' 2005 Wiley-Liss, Inc.

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Section: Drugsmentioning

confidence: 99%

mentioning

confidence: 99%

Combination therapy with 2‐difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma

Chen

Weeks

Burns

et al. 2005

Intl Journal of Cancer

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“…8 The ornithine decarboxylase (ODC) inhibitor, a-di¯uoromethylornithine (DFMO) was obtained from Marion Merrell Dow (Cinncinati, OH).…”

Section: Compoundsmentioning

confidence: 99%

Polyamine depletion therapy in prostate cancer

Devens

Weeks

Burns

et al. 2000

Prostate Cancer Prostatic Dis

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The prostate gland has among the highest level of polyamines in the body and prostate carcinomas have even greater elevated polyamine levels. These ubiquitous molecules synthesized by prostate epithelium are involved in many biochemical processes including cellular proliferation, cell cycle regulation, and protein synthesis. These properties have made polyamines a potential target for therapeutic intervention in diseases of excessive cell proliferation such as cancer. However, attempts to limit tumor growth by inhibition of polyamine synthesis have not been very successful since cells have the capacity to take up polyamines from the bloodstream. We report here studies utilizing polyamine depletion by means of a combination of blockade of polyamine synthesis with DFMO (a-di¯uoromethylornithine), an inhibitor of ornithine decarboxylase, the rate limiting enzyme in the polyamine synthetic pathway, and ORI 1202, a novel inhibitor of polyamine transport into the cell. This cytostatic combination, even in the presence of excess extracellular polyamines, signi®cantly slowed the growth of the human tumor cell line PC-3 grown in tissue culture with an EC 50 in the mM range. Other prostate cell lines were similarly growth inhibited including LNCaP.FGC and DU145. Growth of the PC-3 tumor cell line as a xenograft in nude mice was also slowed signi®cantly by this combination of compounds. Polyamine levels in the tumor were lowered from control tumor levels. This combination therapy could provide an effective and potentially non-toxic therapy for prostate tumors. Prostate Cancer and Prostatic Diseases (2000) 3, 275±279.

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“…The homodimers of putrescine (10) and spermine (15,19) and polymer of spermine (1) have been shown to effectively inhibit PAT. Simple lysine-spermine conjugate (7,46) and lipophilic lysine-spermine (5) also exhibit PAT inhibition activity. 44-Ant-44, the compound shown to have anti-PCP activity in this study, is structurally similar to a spermidine dimer cross-linked by a 9,10-bis-substituted anthraldehyde.…”

Section: Discussionmentioning

confidence: 99%

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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Novel Lysine–Spermine Conjugate Inhibits Polyamine Transport and Inhibits Cell Growth When Given with DFMO

Cited by 48 publications

References 33 publications

Combination therapy with 2‐difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma

Combination therapy with 2‐difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma

Polyamine depletion therapy in prostate cancer

Polyamine Transport as a Target for Treatment ofPneumocystisPneumonia

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