Uptake and cytotoxicity of novel nitroimidazole-polyamine conjugates in ehrlich ascites tumour cells

Holley, Jane L.; Mather, A. N.; Cullis, Paul M.; Symons, Martyn R.; Wardman, Peter; Watt, Robert A.; Cohen, Gerald M.

doi:10.1016/0006-2952(92)90241-a

Cited by 31 publications

(30 citation statements)

References 18 publications

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“…These conjugates have included DNA intercalating agents and alkylating agents such as chlorambucil, acridine and nitroimidazoles [6,[24][25][26][27][28], and also quinines [29], naphtoquinones [30] and topoisomerase I inhibitors such as camptothecin [31]. Overall, several of these conjugates demonstrated favourable in vitro pharmacological properties [32,33].…”

Section: Discussionmentioning

confidence: 99%

Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system

et al. 2009

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We have exploited the polyamine transport system (PTS) to deliver selectively a spermine-drug conjugate, F14512 to cancer cells. This study was aimed to define F14512 anticancer efficacy against tumor models and to investigate whether fluorophor-labeled polyamine probes could be used to identify tumors expressing a highly active PTS and that might be sensitive to F14512 treatments. Eighteen tumor models were used to assess F14512 antitumor activity. Cellular uptake of spermine-based fluorescent probes was measured by flow cytometry in cells sampled from tumor xenografts by needle biopsy. The accumulation of the fluorescent probe within B16 tumors in vivo was assessed using infrared fluorescence imaging. This study has provided evidence of a major antitumor activity for F14512. Significant responses were obtained in 67% of the tumor models evaluated, with a high level of activity recorded in 33% of the responsive models. Complete tumor regressions were observed after i.v., i.p. or oral administrations of F14512 and its antitumor activity was demonstrated over a range of 2-5 dose levels, providing evidence of its good tolerance. The level of cellular fluorescence emitted by the fluorescent probes was higher in cells sampled from tumors sensitive to F14512 treatments than from F14512-refractory tumors. We suggest that these probes could be used to identify tumors expressing a highly active PTS and guide the selection of patients that might be treated with F14512. These results emphasize the preclinical interest of this novel molecule and support its further clinical development.

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Section: Discussionmentioning

confidence: 99%

Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system

et al. 2009

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“…drug. This approach has been applied to the polyamine transporter, polyamine-nitroimidazole conjugate, and polyaminechlorambucil conjugate and has been shown to augment drug accumulation in Erlich-ascites tumors cells with a resulting enhancement of cytotoxicity (44,45). Finally, we have found that chloroquine shares the parasite-induced putrescine transport system in P. knowlesi-infected erythrocytes (46).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Simian Malarial Parasite (Plasmodium knowlesi)-induced Putrescine Transport in Rhesus Monkey Erythrocytes

Singh

Puri

Singh

et al. 1997

Journal of Biological Chemistry

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A stage-dependent increase in the level of putrescine, spermidine, and spermine during intraerythrocytic growth of Plasmodium knowlesi in rhesus monkey erythrocytes was observed. Further, intraerythrocytic P. knowlesi-induced putrescine influx was found in trophozoite stage-infected erythrocytes and process was time-and temperature-dependent and showed saturable kinetics. Characteristics of induced putrescine influx appears in infected erythrocytes to be close to the normal erythrocytes in terms of affinity of putrescine to the putrescine transporter (K m 34.6 ؎ 3.8 M as normal erythrocytes and K m 37.2 ؎ 5.2 M in infected erythrocytes). However, the difference involves the significant increase in the putrescine influx rate after infection (V max ‫؍‬ 4.21 nmol/min/10 10 normal erythrocytes, compared with 11.6 nmol/min/10 10 infected erythrocytes). Energy dependence, involvement of -SH group, and noninterference by amino acid, spermidine, and spermine in the putrescine influx process clearly demonstrate the presence of a distinct transporter for putrescine in infected erythrocytes. A putrescine conjugate N 1 ,N 4 -bis-(7-chloroquinoline-4-yl)butane-1,4-diamine (BCBD) was synthesized, which inhibits the putrescine influx in the P. knowlesi infected erythrocytes (K i of 43.2 M) as well as in vitro growth of P. knowlesi (IC 50 value, 7.64 ؎ 0.97 ng/ml BCBD, 10.8 ؎ 0.45 ng/ml chloroquine). Addition of exogenous polyamines failed to reverse the inhibitory effect of BCBD in vitro. Administration of BCBD (24 mg/kg body weight, intraperitoneal, twice a day for 4 days) cured the Swiss mice infected with multidrugresistant infection of Plasmodium yoelii. Therefore, inhibition of putrescine transport in malaria-infected erythrocytes offers a lead in the search of a new class of chemotherapeutic molecules against malaria.

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“…Based on this, polyamine vectorization was proposed as a valuable strategy to increase the selectivity of anticancer agents. The literature reports several examples of polyamine conjugates with cytotoxic drugs, such as chlorambucil (17), nitroimidazoles (18), aziridines (19), acridines (20), enediyenes (21), anthracenes (16), naphtoquinones (22), camptothecin (23), and protoberberine (24). All these conjugated drugs are DNA-interacting agents used to develop a general strategy by exploiting both the transport mechanism and the high affinity of polyammonium cations for DNA.…”

Section: Introductionmentioning

confidence: 99%

F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

Barret¹,

Kruczynski²,

Vispé³

et al. 2008

Cancer Research

139

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The polyamine transport system (PTS) is an energy-dependent machinery frequently overactivated in cancer cells with a high demand for polyamines. We have exploited the PTS to selectively deliver a polyamine-containing drug to cancer cells. F14512 combines an epipodophyllotoxin core-targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine tail supports three complementary functions: (a) facilitate formulation of a watersoluble compound, (b) increase DNA binding to reinforce topoisomerase II inhibition, and (c) facilitate selective uptake by tumor cells via the PTS. F14512 is 73-fold more cytotoxic to Chinese hamster ovary cells compared with CHO-MG cells with a reduced PTS activity. A decreased sensitivity of L1210 leukemia cells to F14512 was observed in the presence of putrescine, spermidine, and spermine. In parallel, the spermine moiety considerably enhances the drug-DNA interaction, leading to a reinforced inhibition of topoisomerase II. The spermine tail of F14512 serves as a cell delivery vehicle as well as a DNA anchor, and this property translates at the cellular level into a distinct pharmacologic profile. Twentynine human solid or hematologic cell lines were used to characterize the high cytotoxic potential of F14512 (median IC 50 of 0.18 Mmol/L). Finally, the potent antitumor activity of F14512 in vivo was evidenced with a MX1 human breast tumor xenograft model, with partial and complete tumor regressions. This work supports the clinical development of F14512 as a novel targeted cytotoxic drug and sheds light on the concept of selective delivery of drugs to tumor cells expressing the PTS. [Cancer Res 2008;68(23):9845-53]

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Uptake and cytotoxicity of novel nitroimidazole-polyamine conjugates in ehrlich ascites tumour cells

Cited by 31 publications

References 18 publications

Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system

Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system

Characterization of Simian Malarial Parasite (Plasmodium knowlesi)-induced Putrescine Transport in Rhesus Monkey Erythrocytes

F14512, a Potent Antitumor Agent Targeting Topoisomerase II Vectored into Cancer Cells via the Polyamine Transport System

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