The combination of A-966492 and Topotecan for effective radiosensitization on glioblastoma spheroids

Koosha, Fereshteh; Neshasteh-Riz, Ali; Takavar, Abbas; Eyvazzadeh, Nazila; Mazaheri, Zohreh; Eynali, Samira; Mousavi, Mehdi

doi:10.1016/j.bbrc.2017.08.018

Cited by 12 publications

(9 citation statements)

References 26 publications

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“…Correspondingly, the inhibitors of PARP and topoisomerase I enzymes have been extensively investigated to sensitize cancer cells to radiation. As shown in our previous study, the combination usage of A-966492, as a PARP1 inhibitor, and TPT, as a topoisomerase I inhibitor, led to the sensitization of glioblastoma spheroids in the presence of X-ray [20]. In the current study, with the emphasis on targeting approaches to cure glioblastoma tumors, A-966492 and TPT were used in combination with beta-particles of iodine-131 to induce cell death in glioblastoma spheroids.…”

Section: Discussionmentioning

confidence: 52%

“…Hence, the inhibition of PARP1 and PARP2 may leave SSB unrepaired and induce DSB, subsequently leading to radiosensitization and cell death. A-966492, C18H17FN4O, is a dual inhibitor of PARP1 and PARP2 enzymes, which is orally bioavailable and can cross the blood-brain barrier [9,10]. Topotecan (TPT) is derived from Camptothecin and acts as the inhibitor of topoisomerase I.…”

Section: Introductionmentioning

confidence: 99%

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WITHDRAWN: The Effect of Iodine-131 Beta-particles in Combination With A-966492 and Topotecan on Radio-sensitization of Glioblastoma

Koosha

Eynali

Eyvazzadeh

2021

Preprint

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Glioblastoma tumors are resistant to radiotherapy, and the need for drugs to induce radio-sensitization in tumor cells has always been a challenge. Besides, radiotherapy using targeted radionuclide is effective even for resistant tumors. Poly (ADP-ribose) polymerase (PARP) and topoisomerase I enzymes have critical roles in the repairmen of DNA damage in cells. Thus, the inhibition of the activity of these enzymes can prevent the process of DNA repair and lead to the accumulation of damaged DNA in cells, resulting in the induction of cell death in tumors. In the current study, we investigated the effect of beta-particles of iodine-131 in combination with Topotecan (TPT), as the inhibitor of topoisomerase I, and A-966492, as the inhibitor of the PARP enzyme to increase radio-sensitivity of glioblastoma cells.The U87MG cell line (a human glioblastoma cell line) were cultured in Poly-Hema-coated flasks to reach 300μm-diameter spheroids. Then, the cells were treated with non-toxic concentrations of A-966492 and TPT. The viability of the cells treated with iodine131 in combination with A-966492 and TPT was determined by the clonogenic assay. The expression level of the gamma-H2AX protein, as a biomarker of DNA double-strand breaks, was measured by the immunofluorescence staining method to examine the impact of A-966492 (1μM), TPT, and radiation on the induction cell death.The combination of A-966492 and TPT with radiation resulted in the enhanced cell death, and sensitizer enhancement ratios at 50% survival (SER50) were 1.25 and 1.45, respectively. Radio- and chemo-sensitization were promoted when iodine-131 was combined with A-966492 and TPT, with the SER50 of 1.68. Also, the expression of γ-H2AX was significantly increased in cells treated with A-966492 and TPT combined with radiation.The results demonstrated that iodine-131, in combination with A-966492 and TPT, had marked effects on radio-sensitizing and can be used as a targeted radionuclide for targeting radiotherapy in combination with PARP and topoisomerase I inhibitors to improve radiotherapy in clinics.

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Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The Effect of Iodine-131 Beta-particles in Combination With A-966492 and Topotecan on Radio-sensitization of Glioblastoma

Koosha

Eynali

Eyvazzadeh

2021

Preprint

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“…Although the mechanism is unclear, the radiosensitizing effect may relate to accumulation of cells in S phase and inhibition of DNA repair 10 . When topotecan is administered by intraventricular route in humans at the MTD of 0.4 mg, the AUC is 21 micromolar‐hour, T 1/2α is 26 ± 9 minutes, and T 1/2β is 174 ± 72 minutes 5,10,14 …”

Section: Discussionmentioning

confidence: 99%

“…2,3 In preclinical and clinical studies, TOPO has demonstrable radiation-sensitizing effects in multiple solid tumor histologies, including breast carcinoma, 10,11 and in patients with brain metastases. 10,12,13 Although the mechanism is unclear, the radiosensitizing effect may relate to accumulation of cells in S phase and inhibition of DNA repair. 10 When topotecan is administered by intraventricular route in humans at the MTD of 0.4 mg, the AUC is 21 micromolar-hour, T 1/2α is 26 ± 9 minutes, and T 1/2β is 174 ± 72 minutes.…”

Section: Discussionmentioning

confidence: 99%

“…10,12,13 Although the mechanism is unclear, the radiosensitizing effect may relate to accumulation of cells in S phase and inhibition of DNA repair. 10 When topotecan is administered by intraventricular route in humans at the MTD of 0.4 mg, the AUC is 21 micromolar-hour, T 1/2α is 26 ± 9 minutes, and T 1/2β is 174 ± 72 minutes. 5,10,14 Following intra-CSF treatment of patients with LM and breast cancer, survival has typically ranged from 2.9-5.4 months, 4,[15][16][17][18][19][20][21][22][23][24] and up to 13.6 months in HER2+ patients treated with intra-CSF trastuzumab.…”

Section: Discussionmentioning

confidence: 99%

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Intra‐CSF topotecan in treatment of breast cancer patients with leptomeningeal metastases

et al. 2020

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Background There are few treatment options for patients with leptomeningeal metastases (LM). Methods We report a case series of patients with breast cancer and LM treated with intra‐CSF topotecan (TOPO). Outcome was assessed by clinical exam and MRI at baseline, at end of induction (4‐5 weeks), then every 3 months; CSF cytology was determined at baseline and with each treatment. Results Thirty‐one women [median age, 58 (37‐81); median KPS 60 (40‐100)] received treatment. At baseline, 68% had positive CSF cytology, and 90%, leptomeningeal enhancement on MRI. 84% of patients also received focal RT (not during TOPO) and 77% received concomitant systemic hormonal or chemotherapy. Median number of TOPO treatments was 14.5 (range, 3‐71); median duration of treatment, 11 weeks (1‐176); and median OS, 6.9 months (range, 0.9‐48.8). Patients remaining progression‐free during 4‐6 weeks of induction (81%) had a median OS of 11.5 months (range, 1.8‐48.8). Overall neurologic PFS at 6, 12, and 24 months was 39%, 26%, and 6%, respectively. Clearing of CSF malignant cells for >3 consecutive samples occurred in 10/21 (48%) patients with positive CSF cytology at baseline, remaining clear for a median duration of 15.9 months (range, 1.4‐34.5). Grade 3 adverse events included headache or vomiting (3pts), T2 hyperintensity surrounding the ventricular catheter (2 pts), and meningitis (2 pts). Conclusions Intra‐CSF TOPO, with focal RT as needed for symptomatic areas of enhancement produced durable clearing of CSF malignant cells in 48% of patients positive at baseline, with promising median PFS and OS.

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The DNA Double-Strand Break Repair in Glioma: Molecular Players and Therapeutic Strategies

Maksoud

2022

Mol Neurobiol

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The combination of A-966492 and Topotecan for effective radiosensitization on glioblastoma spheroids

Cited by 12 publications

References 26 publications

WITHDRAWN: The Effect of Iodine-131 Beta-particles in Combination With A-966492 and Topotecan on Radio-sensitization of Glioblastoma

WITHDRAWN: The Effect of Iodine-131 Beta-particles in Combination With A-966492 and Topotecan on Radio-sensitization of Glioblastoma

Intra‐CSF topotecan in treatment of breast cancer patients with leptomeningeal metastases

The DNA Double-Strand Break Repair in Glioma: Molecular Players and Therapeutic Strategies

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The combination of A-966492 and Topotecan for effective radiosensitization on glioblastoma spheroids

Cited by 12 publications

References 26 publications

WITHDRAWN: The Effect of Iodine-131 Beta-particles in Combination With A-966492 and Topotecan&nbsp;on Radio-sensitization of Glioblastoma

WITHDRAWN: The Effect of Iodine-131 Beta-particles in Combination With A-966492 and Topotecan&nbsp;on Radio-sensitization of Glioblastoma

Intra‐CSF topotecan in treatment of breast cancer patients with leptomeningeal metastases

The DNA Double-Strand Break Repair in Glioma: Molecular Players and Therapeutic Strategies

Contact Info

Product

Resources

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WITHDRAWN: The Effect of Iodine-131 Beta-particles in Combination With A-966492 and Topotecan on Radio-sensitization of Glioblastoma

WITHDRAWN: The Effect of Iodine-131 Beta-particles in Combination With A-966492 and Topotecan on Radio-sensitization of Glioblastoma