RESUMO
BACKGROUND: Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. METHODS AND FINDINGS: This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. CONCLUSIONS: Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01310855.
Assuntos
Antineoplásicos/uso terapêutico , Progressão da Doença , Glioblastoma/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Receptores ErbB/metabolismo , Feminino , Gefitinibe , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Placebos , Qualidade de Vida , Quinazolinas/efeitos adversos , Recidiva , Segurança , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Only four drugs are available for chemotherapy of human African sleeping sickness with undesirable toxic side effects. The development of new anti-trypanosomal drugs is, therefore, urgently required. In this study, 15 DNA topoisomerase inhibitors, including approved anti-cancer drugs, were tested for in vitro activity against bloodstream forms of Trypanosoma brucei and human leukaemia HL-60 cells. All compounds exhibited anti-trypanosomal activity, with ED50 values ranging between 3 nM and 30 microM, and MIC values between 100 nM and >100 microM. The trypanocidal activities of the most effective DNA topoisomerase inhibitors, aclarubicin, doxorubicin and mitoxantrone, were comparable with those of commercial anti-trypanosomal drugs. These data support the use of DNA topoisomerase inhibitors as lead compounds for anti-trypanosomal drug development.
Assuntos
Antiprotozoários/uso terapêutico , Inibidores da Topoisomerase I , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Animais , Células HL-60 , Humanos , Testes de Sensibilidade MicrobianaRESUMO
Glioblastoma multiforme (GBM) are the most common primary brain tumor and are resistant to standard therapies. The nondividing nature of normal brain provides an opportunity to enhance the therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair pathways. Based on our previous findings that inhibition of poly(ADP-ribose) polymerase (PARP) increases radiosensitivity of human glioma cells in a replication-dependent manner and generates excess DNA breaks that are repaired by homologous recombination (HR), we hypothesized that inhibition of HR would amplify the replication-specific radiosensitizing effects of PARP inhibition. Specific inhibitors of HR are not available, but the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) has been reported to inhibit HR function. The radiosensitizing effects of 17-AAG and the PARP inhibitor olaparib were assessed, and the underlying mechanisms explored. 17-AAG down-regulated Rad51 and BRCA2 protein levels, abrogated induction of Rad51 foci by radiation, and inhibited HR measured by the I-Sce1 assay. Individually, 17-AAG and olaparib had modest, replication-dependent radiosensitizing effects on T98G glioma cells. Additive radiosensitization was observed with combination treatment, mirrored by increases in gammaH2AX foci in G(2)-phase cells. Unlike olaparib, 17-AAG did not increase radiation sensitivity of Chinese hamster ovary cells, indicating tumor specificity. However, 17-AAG also enhanced radiosensitivity in HR-deficient cells, indicating that its effects were only partially mediated by HR inhibition. Additional mechanisms are likely to include destabilization of oncoproteins that are up-regulated in GBM. 17-AAG is therefore a tumor-specific, replication-dependent radiosensitizer that enhances the effects of PARP inhibition. This combination has therapeutic potential in the management of GBM.
Assuntos
Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases , Radiossensibilizantes , Animais , Benzoquinonas/farmacologia , Neoplasias Encefálicas/enzimologia , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Inibidores Enzimáticos/farmacologia , Glioblastoma/enzimologia , Proteínas de Choque Térmico HSP90/metabolismo , Células HeLa , Humanos , Lactamas Macrocíclicas/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Tolerância a Radiação , Recombinação GenéticaRESUMO
PURPOSE: Current treatments for glioblastoma multiforme are inadequate and limited by the radiation sensitivity of normal brain. Because glioblastoma multiforme are rapidly proliferating tumors within nondividing normal tissue, the therapeutic ratio might be enhanced by combining radiotherapy with a replication-specific radiosensitizer. KU-0059436 (AZD2281) is a potent and nontoxic inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) undergoing a Phase II clinical trial as a single agent. METHODS AND MATERIALS: Based on previous observations that the radiosensitizing effects of PARP inhibition are more pronounced in dividing cells, we investigated the mechanisms underlying radiosensitization of human glioma cells by KU-0059436, evaluating the replication dependence of this effect and its therapeutic potential. RESULTS: KU-0059436 increased the radiosensitivity of four human glioma cell lines (T98G, U373-MG, UVW, and U87-MG). Radiosensitization was enhanced in populations synchronized in S phase and abrogated by concomitant exposure to aphidicolin. Sensitization was further enhanced when the inhibitor was combined with a fractionated radiation schedule. KU-0059436 delayed repair of radiation-induced DNA breaks and was associated with a replication-dependent increase in gammaH2AX and Rad51 foci. CONCLUSION: The results of our study have shown that KU-0059436 increases radiosensitivity in a replication-dependent manner that is enhanced by fractionation. A mechanism is proposed whereby PARP inhibition increases the incidence of collapsed replication forks after ionizing radiation, generating persistent DNA double-strand breaks. These observations indicate that KU-0059436 is likely to enhance the therapeutic ratio achieved by radiotherapy in the treatment of glioblastoma multiforme. A Phase I clinical trial is in development.