Activity of Antitumor Drugs Against African Trypanosomes

Kinnamon, Kenneth E.; Steck, Edgar A.; Rane, Dora S.

doi:10.1128/aac.15.2.157

Cited by 73 publications

(34 citation statements)

References 6 publications

(9 reference statements)

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“…Several antitumor agents directed towards DNA as their molecular target have been screened for their Parasite, 2000, 7, 103-108trypanocidal activity, since the metabolic pathways of Kinetoplastidae and tumor cells present some similarities. By this means, organometallic complexes were found to have antitrypanosomal activity (Kinnamon et al, 1979). The association of a metallic structure with an organic compound decreases the toxicity and usually increases the biological activity (Fanell et al, 1984).…”

Section: L'action Antileishmanienne Du Tétraphénylborate D'ir-(cod)-pmentioning

confidence: 99%

In vivoantileishmanial action of Ir-(COD)-pentamidine tetraphenylborate onLeishmania donovaniandLeishmania majormouse models

et al. 2000

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Summary:lr-(COD)-pentamidine tetraphenylborate which has previously been studied on promastigote forms of Leishmania, was investigated for its antileishmanial properties compared with pentamidine used as reference compound. In vitro, the iridium complex had the same IC 50 value on intracellular forms of Leishmania as pentamidine (15 µM). In vivo, the compound could not be injected intravenously due to the DMSO excipient so that the treatments were performed intraperitoneally or subcutaneously. On the L. donovani LV9 /Balb/C mouse model, the iridium complex was not toxic after intraperitoneal treatment at 232 mg/kg/day x 5 or 147 µmoles/ kg/day x 5, whereas all the mice died within five days when treated at the same dose with pentamidine isethionate. However, only 23 % of parasite suppression was observed with the iridium complex. On a L. major MON 74/Balb/C mouse model, susceptible to intravenously administered pentamidine at 6.7 umoles/ kg/day x 5 (54 % of parasite suppression), the iridium complex exhibited 32 % of parasite suppression after a treatment at 76 umoles/ kg/day x 5 administered subcutaneously. This slight activity is of interest since pentamidine isethionate is not active under these conditions. Transmission electron microscopy of amastigotes from infected and treated mice show aggregation of ribosomal material, distension of the nuclear membrane and kDNA depolymerization. The mechanism of action therefore involves several targets: membranes, ribosomes and kDNA. According to our results, the Iridium complex is a suitable candidate to be encapsulated in drug carriers such as liposomes or nanoparticles.KEYWORDS : Iridium pentamidine complex, pentamidine, Leishmania, electron microscopy, mechani sm of action. MOTS CLÉS

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Section: L'action Antileishmanienne Du Tétraphénylborate D'ir-(cod)-pmentioning

confidence: 99%

In vivoantileishmanial action of Ir-(COD)-pentamidine tetraphenylborate onLeishmania donovaniandLeishmania majormouse models

et al. 2000

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“…3,4 Cisplatin and other metal-containing antitumoral compounds have been tested against Leishmania spp with interesting results in the search for new and more effective chemotherapeutic treatments. Based on these results and because it is known that this kind of compound interacts with DNA, it has been proposed that all DNA-interacting compounds might show activity against protozoa.…”

Section: Introductionmentioning

confidence: 99%

Palladium polypyridyl complexes: synthesis, characterization, DNA interaction and biological activity on Leishmania (L.) mexicana

Navarro¹,

Betancourt²,

Hernández³

et al. 2008

J. Braz. Chem. Soc.

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Este trabalho descreve a busca de novos agentes com potencial quimioterápico baseados em complexos de metais de transição com ligantes planares. Neste estudo, complexos polipiridilpaládio foram sintetizados e caracterizados por análise elementar e por espectroscopias de RMN e de absorção no UV-visível e no infravermelho. A interação dos complexos com DNA também foi investigada por métodos espectroscópicos. Todas as bandas de transferência de carga do metal para os ligantes (TCML) dos complexos polipiridilpaládio exibiram hipocromismo e deslocamento para o vermelho na presença de DNA.

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“…It also effects significant increases in survival of mice infected with Trypanosoma rhodesiense when administered at maximum tolerated doses (4). Recently, Wysor and co-workers were able to cure T. rhodesiense-infected mice with CDDP.…”

mentioning

confidence: 92%

Capacity of a cis-diammineplatinum[II]-polyglutamic acid complex to cure Trypanosoma congolense infections in mice

Meshnick¹,

Brown²,

Smith³

1984

Antimicrob Agents Chemother

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A cis-diammineplatinum(II)-polyglutamic acid complex proved to have marked trypanocidal activity in vivo. When 5 mg of platinum per kg was administered daily for 5 days or when 20 mg of platinum per kg was administered on days 1, 3, and 6, five of five treated Trypanosoma congolense-infected mice were cured. In contrast, cis-platin was ineffective at all doses tested. We believe that the complex has a much higher therapeutic ratio than does uncomplexed drug because it is less toxic.Cis-platin (CDDP) is an anticancer drug with demonstrable activity against a broad spectrum of human tumors (7). It also effects significant increases in survival of mice infected with Trypanosoma rhodesiense when administered at maximum tolerated doses (4). Recently, Wysor and co-workers were able to cure T. rhodesiense-infected mice with CDDP. They accomplished this by reducing the toxicity of CDDP with hydration and coadministration of the chelator diethyldithiocarbamate and were thus able to administer doses of the drug which would have ordinarily been lethal (9).In this report we have taken a different approach and followed the lead of Williamson and Scott-Finnigan who treated T. rhodesiense-infected mice with daunorubicin complexed to macromolecules to reduce the toxicity of daunorubicin (8). Accordingly, we prepared a macromolecular derivative of CDDP in which cis-diammineplatinum(II) (DP) was bound to polyglutamic acid (PGA). We report here that this complex effected cures of T. congolense-infected mice at tolerated doses.T. congolense TREU 1183 (6) was maintained by serial passage in Rockefeller NCS mice. For evaluation of antitrypanosomal activity, freshly obtained infected blood was diluted with minimal essential medium and counted by phase-contrast microscopy with a Petroff-Hauser cell counter. Mice utilized in assessments of therapeutic activity were inoculated with 105 organisms intraperitoneally. They were then randomized into treatment groups of five mice each and a control group of at least 10 mice. Compounds were dissolved in normal saline except for CDDP, which was not soluble. This latter compound was suspended in normal saline and then sonicated. All drugs were administered intraperitoneally.DP-PGA was synthesized by a two-step process. A solution of cis-Pt(NH3)2(NO3)2 was prepared by reacting AgNO3 (14.34 g) with CDDP (12.0 g) in 100 ml of distilled water at room temperature for 16 h and filtered. Two milliliters of the filtrate was then added to 0.5 g of PGA (sodium salt; weight average molecular weight, 50,000; Sigma Chemical Co., St. Louis, Mo.) in 210 ml of distilled water at room temperature. The reaction mixture was stirred for 20 h and then dialyzed for 6 h (dialysis tubing molecular weight cutoff, 5,000 to 6,000) to remove NaNO3 and unreacted cis-Pt(NH3)2(NO2)2. * Corresponding author.The resulting reaction product contained 0.61% bound platinum as determined by atomic absorption. Infrared spectroscopy of the lyophilized compound confirmed the presence of platinum-carboxyl moiety bonds (unpublished data)....

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Activity of Antitumor Drugs Against African Trypanosomes

Cited by 73 publications

References 6 publications

In vivoantileishmanial action of Ir-(COD)-pentamidine tetraphenylborate onLeishmania donovaniandLeishmania majormouse models

In vivoantileishmanial action of Ir-(COD)-pentamidine tetraphenylborate onLeishmania donovaniandLeishmania majormouse models

Palladium polypyridyl complexes: synthesis, characterization, DNA interaction and biological activity on Leishmania (L.) mexicana

Capacity of a cis-diammineplatinum[II]-polyglutamic acid complex to cure Trypanosoma congolense infections in mice

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