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Pharmacogenetics of ATP binding cassette transporter MDR1(1236C>T) gene polymorphism with glioma patients receiving Temozolomide-based chemoradiation therapy in Indian population

The Pharmacogenomics Journal volume 21, pages 262–272 (2021)Cite this article

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Abstract

Temozolomide (TMZ), an alkylating agent with a broad-spectrum antitumor activity, ability to cross blood–brain barrier (BBB), shown to be effective against malignant glioma. This study aims to investigate the effect of 1236C>T (rs1128503) single-nucleotide gene polymorphisms of ABCB1 (MDR1) in north-Indian patients diagnosed with glioma undergoing TMZ-based chemoradiotherapy. Genotyping was performed in 100 patients diagnosed with malignant glioma (50 anaplastic astrocytoma (AA) patients and 50 glioblastoma multiforme (GBM) patients) and 150 age and sex-matched controls by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method, followed by sanger sequencing. TMZ plasma levels were analyzed by reverse phase HPLC method. Glioma patient’s survival time was analyzed by Kaplan–Meier’s curve. Results of MDR1 gene 1236C>T polymorphism showed significant allelic and genotypic frequency association between glioma patients and controls. The plasma TMZ levels between metabolizers group in Grade III and Grade IV were found to be statistically significant (p < 0.05). The mutant genotype (TT) has less survival benefit compared with other genotypes (CT/CC) and the survival difference between AA and GBM was found to be statistically significant (p < 0.05). Though CT and TT polymorphisms have significant association with lower TMZ levels in both Grade III (AA) and IV (GBM) tumors, the survival difference seems to be mainly among patients with Grade III tumors. Our findings suggest that the MDR1 gene polymorphism plays a role in plasma TMZ levels and in survival time of glioma patients and, hence, TMZ therapy in malignant glioma can be predicted by genotyping MDR1 (1236C>T) gene polymorphism.

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Fig. 1: MDR1 (1236C>T) PCR-RFLP pattern.
Fig. 2: Sequencing analysis for MDR1 1236C>T polymorphism.
Fig. 3: HPLC chromatogram of TMZ and caffeine (IS).
Fig. 4: Concentration of TMZ vs response.
Fig. 5: Correlation of plasma TMZ levels in glioma patients with MDR1 gene 1236C>T polymorphism.
Fig. 6: Kaplan–Meier’s survival analysis of glioma patients with MDR1 1236C>T polymorphism.

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Acknowledgements

The authors thank patients and controls for their participation in this project. The author SM thank All India Institute of Medical Sciences, New Delhi for providing Institute fellowship during Ph.D. programme. The authors thank Dr. Vanamail and Dr. Amit Kumar, All India Institute of Medical Sciences, New Delhi for statistical support.

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  1. These authors contributed equally: Murali Munisamy, Srinivasan Munisamy

Authors and Affiliations

  1. Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India

    Murali Munisamy, Anmi Jose, Levin Thomas & Gayathri Baburaj

  2. Department of Neuro Biochemistry, Neuroscience Centre, All India Institute of Medical Sciences, New Delhi, India

    Murali Munisamy, Srinivasan Munisamy & Vivekanandhan Subbiah

  3. Department of Radiotherapy, Dr. B.R.A Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India

    Julka Pramod Kumar

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Munisamy, M., Munisamy, S., Kumar, J.P. et al. Pharmacogenetics of ATP binding cassette transporter MDR1(1236C>T) gene polymorphism with glioma patients receiving Temozolomide-based chemoradiation therapy in Indian population. Pharmacogenomics J 21, 262–272 (2021). https://doi.org/10.1038/s41397-021-00206-y

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