Phase I and pharmacokinetic study of the water-soluble dolastatin 15 analog LU103793 in patients with advanced solid malignancies.

Villalona‐Calero, Miguel A.; Baker, Sharyn D.; Hammond, Lisa A.; Aylesworth, Cheryl; Eckhardt, S. Gail; Kraynak, Maura A.; Fram, Robert J.; Fischkoff, Steven A.; Velagapudi, Raja; Toppmeyer, Deborah; Razvillas, Betty; Jakimowicz, K; Hoff, Daniel D. Von; Rowinsky, Eric K.

doi:10.1200/jco.1998.16.8.2770

Cited by 32 publications

(11 citation statements)

References 9 publications

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“…Tasidotin is converted intracellularly to P5, as was reported (de Aruda et al, 1995; Mross et al, 1996, 1998; Supko et al, 2000; Villalono-Calero et al, 1998), but not documented in the literature, for cemadotin. As recently shown by Ray et al (2007), P5 was more active than tasidotin as an inhibitor of tubulin assembly but less active as a cytotoxic agent.…”

Section: Discussionmentioning

confidence: 58%

“…The cemadotin literature often refers to its intracellular metabolism to P5, which is described as having equivalent or greater activity with tubulin than the parent compound (de Aruda et al, 1995; Mross et al, 1996, 1998; Villalono-Calero et al, 1998; Supko et al, 2000). To our knowledge, studies documenting this transformation or the activity of cemadotin-derived P5 against tubulin were never published.…”

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confidence: 99%

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Intracellular Activation and Deactivation of Tasidotin, an Analog of Dolastatin 15: Correlation with Cytotoxicity

Bai¹,

Edler²,

Bonate³

et al. 2008

Mol Pharmacol

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Tasidotin, an oncolytic drug in phase II clinical trials, is a peptide analog of the antimitotic depsipeptide dolastatin 15. In tasidotin, the carboxyl-terminal ester group of dolastatin 15 has been replaced by a carboxy-terminal tert-butyl amide. As expected from studies with cemadotin, [ 3 H]tasidotin, with the radiolabel in the second proline residue, was hydrolyzed intracellularly, with formation of N, N-dimethylvalyl-valyl-N-methylvalyl-prolyl-proline (P5), a pentapeptide also present in dolastatin 15 and cemadotin. P5 was more active as an inhibitor of tubulin polymerization and less active as a cytotoxic agent than tasidotin, cemadotin, and dolastatin 15. [ 3 H]P5 was not the end product of tasidotin metabolism. Large amounts of [ 3 H]proline were formed in every cell line studied, with proline ultimately becoming the major radiolabeled product. The putative second product of the hydrolysis of P5, N,N-dimethylvalyl-valyl-N-methylvalyl-proline (P4), had little activity as either an antitubulin or cytotoxic agent. In seven suspension cell lines, the cytotoxicity of tasidotin correlated with total cell uptake of the compound and was probably affected negatively by the extent of degradation of P5 to proline and, presumably, P4. The intracellular enzyme prolyl oligopeptidase probably degrades tasidotin to P5. When CCRF-CEM human leukemia cells were treated with N-benzyloxycarbonylprolylprolinal (BCPP), an inhibitor of prolyl oligopeptidase, there was a 30-fold increase in the IC 50 of tasidotin and a marked increase in intracellular [ 3 H]tasidotin. BCPP also caused a 4-fold increase in the IC 50 of P5, so the enzyme probably does not convert P5 to P4. Inhibiting degradation of P5 should have led to a decrease in the IC 50 obtained for P5 in the presence of BCPP. Fig. 1) are unusual antitubulin agents. Despite relatively feeble interactions with tubulin, the most active compounds have exceptional cytotoxicity with IC 50 values often in the high picomolar or low nanomolar range (Pettit et al Dolastatin 15 and its analogs (structures in

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Section: Discussionmentioning

confidence: 58%

mentioning

confidence: 99%

Intracellular Activation and Deactivation of Tasidotin, an Analog of Dolastatin 15: Correlation with Cytotoxicity

Bai¹,

Edler²,

Bonate³

et al. 2008

Mol Pharmacol

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“…Nos testes clínicos, a cemadotina (Quadro 3) mostrou-se segura nos estudos de fase 1 e melhorou a qualidade de vida de alguns pacientes com câncer de pulmão em fase 2, porém não demonstrou resultados objetivos contra os tumores. [119][120][121][122][123][124][125][126][127] A sintadotina (Quadro 3) é uma dolastatina de 3 a geração que age estabilizando microtúbulos, porém com um mecanismo singular, distinto das outras dolastatinas ou mesmo dos taxanos. O ILX-651 traz grandes vantagens, como ser ativo por via oral e possuir uma janela terapêutica maior que a da cemadotina.…”

Section: Tipo De Câncer Fase De Estudo Clínico 1 2unclassified

Organismos marinhos como fonte de novos fármacos: histórico & perspectivas

Costa-Lotufo¹,

Wilke²,

Jimenez³

et al. 2009

Quím. Nova

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Recebido em 15/1/09; aceito em 11/3/09; publicado na web em 2/4/09 MARINE ORGANISMS AS A SOURCE OF NEW PHARMACEUTICALS: HISTORY AND PERSPECTIVES. Though sharing only a short part on the natural products timeline, the studies on marine products has already handed in four new drugs to the clinical arsenal and brought up a long and promising list of unique molecules to pre-clinical and clinical trials. Thus, as the available analytical resources improve and the interest of large pharmaceutical companies arises, medical use of marine products has definitely become a reality.Keywords: marine biotechnology; natural products; marine drugs. intrOdUÇÃOOs produtos naturais têm sido a maior fonte de inspiração para diversas áreas da química e da ciência de um modo geral. Usando, copiando ou modificando as moléculas sintetizadas pelos seres vivos, o homem tem obtido inovações para o seu benefício em diversas áreas e, entre elas, a produção de fármacos. Do analgésico morfina, ao antibiótico penicilina, passando pelo anticâncer paclitaxel (Taxol ® ), estima-se que 80% dos fármacos em uso são produtos naturais ou foram inspirados pela natureza.Existem várias revisões recentes que podem ser consultadas para uma visão da contribuição dos produtos naturais na indústria farmacêutica. 1-4 Neste contexto, os organismos terrestres (principalmente micro-organismos e plantas) são os responsáveis por quase a totalidade dessas substâncias, enquanto que os organismos marinhos, apesar de promissores, passaram a ser investigados de maneira sistemática apenas recentemente. Nesta breve revisão comentaremos alguns aspectos históricos dos estudos químicos e farmacológicos realizados com organismos marinhos e suas implicações científicas, como a descoberta de novos produtos naturais com ação em alvos moleculares peculiares, além da utilização desse conhecimento pela indústria farmacêutica no processo de pesquisa e desenvolvimento (P&D) de fármacos.históricO Mares e oceanos ocupam mais de 2/3 da superfície da Terra e abrigam quase todos os grupos de organismos vivos, incluindo representantes de 34 dentre os 36 filos descritos. Sendo assim, os ecossistemas marinhos podem ser considerados como detentores da maior biodiversidade filética, com potencial biotecnológico associado praticamente ilimitado. [5][6][7][8] Até os anos 50, este ecossistema escapou do interesse dos cientistas de produtos naturais, principalmente devido ao difícil acesso às suas profundidades. Com o avanço das técnicas e o advento dos equipamentos seguros de mergulho, na década de 70, algas e invertebrados marinhos puderam dar início às suas histórias nas bancadas dos laboratórios de química e farmacologia. 7 O pesquisador Werner Bergmann da Universidade de Yale (E.U.A.) foi um dos pioneiros, na década de 50, no estudo dos produtos naturais marinhos. Um dos exemplos históricos no desenvolvimento de fármacos marinhos teve origem no seu trabalho de isolamento dos nucleosídeos espongouridina (1) e espongotimidina (2) da esponja Tethya crypta (Cryptotethya crypta). 9 Análogos sintét...

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“…Dolastatin10 and 15 showed the most promising antimitotic activity and both have entered clinical trial. Earlier, the discovery of dolastatin 3-15 had been reviewed [279] and SAR, synthesis and pharmacological properties of these agents have been described [280] .…”

Section: Dolastatin and Its Derivativesmentioning

confidence: 99%

Microtubulin Binding Sites as Target for Developing Anticancer Agents

Islam¹,

Iskander²

2004

MRMC

131

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Microtubules (MTs) play important and diverse roles in eukaryotic cells. Their function and biophysical properties have made alpha-and beta-tubulin, the main components of MTs, the subject of intense study. Interfering with normal MT dynamics, for example, by the addition of tubulin ligands, can cause the cell great distress and affect MT stability and functions, including mitosis, cell motion and intracellular organelle transport. It has been shown in the literature that tubulin is an important target molecule for developing anticancer drugs. Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. This mode of action is also shared with other natural agents eg colchicine and podophyllotoxin. However various tubulin isotypes have shown resistance to taxanes and other MT agents. Therefore, there is a strong need to design and develop new natural analogs as antimitotic agents to interact with tubulin at sites different from those of vinca alkaloids and taxanes. This minireview provides SAR on several classes of antimitotic agents reported in the literature. The structures and data given are essential to the scientists who are involved in drug design and development in the field of anticancer drugs.

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Phase I and pharmacokinetic study of the water-soluble dolastatin 15 analog LU103793 in patients with advanced solid malignancies.

Cited by 32 publications

References 9 publications

Intracellular Activation and Deactivation of Tasidotin, an Analog of Dolastatin 15: Correlation with Cytotoxicity

Intracellular Activation and Deactivation of Tasidotin, an Analog of Dolastatin 15: Correlation with Cytotoxicity

Organismos marinhos como fonte de novos fármacos: histórico & perspectivas

Microtubulin Binding Sites as Target for Developing Anticancer Agents

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