Bisht Priya, Kumar V Udaya, Pandey Ruchi, Velayutham Ravichandiran, Kumar Nitesh
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India.
Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER-Hajipur), Hajipur, India.
Front Pharmacol. 2022 Jul 6;13:939570. doi: 10.3389/fphar.2022.939570. eCollection 2022.
Glioblastoma multiform is the most aggressive primary type of brain tumor, representing 54% of all gliomas. The average life span for glioblastoma multiform is around 14-15 months instead of treatment. The current treatment for glioblastoma multiform includes surgical removal of the tumor followed by radiation therapy and temozolomide chemotherapy for 6.5 months, followed by another 6 months of maintenance therapy with temozolomide chemotherapy (5 days every month). However, resistance to temozolomide is frequently one of the limiting factors in effective treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been investigated as sensitizing drugs to enhance temozolomide potency. However, clinical use of PARP inhibitors in glioblastoma multiform is difficult due to a number of factors such as limited blood-brain barrier penetration of PARP inhibitors, inducing resistance due to frequent use of PARP inhibitors, and overlapping hematologic toxicities of PARP inhibitors when co-administered with glioblastoma multiform standard treatment (radiation therapy and temozolomide). This review elucidates the role of PARP inhibitors in temozolomide resistance, multiple factors that make development of these PARP inhibitor drugs challenging, and the strategies such as the development of targeted drug therapies and combination therapy to combat the resistance of PARP inhibitors that can be adopted to overcome these challenges.
多形性胶质母细胞瘤是最具侵袭性的原发性脑肿瘤类型，占所有胶质瘤的54%。多形性胶质母细胞瘤未经治疗的平均寿命约为14 - 15个月。目前多形性胶质母细胞瘤的治疗方法包括手术切除肿瘤，随后进行6.5个月的放射治疗和替莫唑胺化疗，之后再进行6个月的替莫唑胺维持化疗（每月5天）。然而，对替莫唑胺的耐药性常常是有效治疗的限制因素之一。聚（ADP - 核糖）聚合酶（PARP）抑制剂最近被研究作为增敏药物以增强替莫唑胺的效力。然而，由于多种因素，如PARP抑制剂血脑屏障穿透性有限、频繁使用PARP抑制剂导致耐药以及PARP抑制剂与多形性胶质母细胞瘤标准治疗（放射治疗和替莫唑胺）联合使用时存在重叠的血液学毒性，PARP抑制剂在多形性胶质母细胞瘤中的临床应用存在困难。本综述阐明了PARP抑制剂在替莫唑胺耐药中的作用、使这些PARP抑制剂药物研发具有挑战性的多种因素，以及可采用的如开发靶向药物疗法和联合疗法等策略，以对抗PARP抑制剂的耐药性从而克服这些挑战。
