Via Research Recognition Day Program VCOM-Carolinas 2025

Biomedical Research

The Impact of Pharmacogenomics in Antimetabolite Therapy Regimens Using the Antimetabolites Clofarabine, Pentostatin, or Nelarabine

Zachary T. Fitzgerald, B.S. 1 , Steven Enkemann, PhD 2 Edward Via College of Osteopathic Medicine, Spartanburg, SC.

Introduction

Results

Discussion

References 1. Nagai S, Takenaka K, Nachagari D, Rose C, Domoney K, Sun D, Sparreboom A, Schuetz JD. Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity. Cancer Res. 2011 Mar 1;71(5):1781-91. doi: 10.1158/0008-5472.CAN-10-1919. Epub 2011 Jan 18. PMID: 21245102; PMCID: PMC3531552. 2. Huang M, Inukai T, Miyake K, Tanaka Y, Kagami K, Abe M, Goto H, Minegishi M, Iwamoto S, Sugihara E, Watanabe A, Somazu S, Shinohara T, Oshiro H, Akahane K, Goi K, Sugita K. Clofarabine exerts antileukemic activity against cytarabine-resistant B-cell precursor acute lymphoblastic leukemia with low deoxycytidine kinase expression. Cancer Med. 2018 Apr;7(4):1297-1316. doi: 10.1002/cam4.1323. Epub 2018 Feb 23. PMID: 29473342; PMCID: PMC5911575. 3. Zhang, H., Liu, R., Lou, T., Zhao, P., & Wang, S. (2022). Pentostatin Biosynthesis Pathway Elucidation and Its Application. Fermentation , 8 (9), 459. https://doi.org/10.3390/fermentation8090459 4. Fukuda Y, Schuetz JD. ABC transporters and their role in nucleoside and nucleotide drug resistance. Biochem Pharmacol. 2012 Apr 15;83(8):1073-83. doi: 10.1016/j.bcp.2011.12.042. Epub 2012 Jan 20. PMID: 22285911; PMCID: PMC3319017. 5. Choudhuri S, Klaassen CD. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol. 2006 Jul-Aug;25(4):231-59. doi: 10.1080/10915810600746023. PMID: 16815813. Special thank you to the Edward Via College of Osteopathic Medicine – Carolinas library team for aiding in the compilation of source material. Acknowledgements Wn ehl ai lrea bt hi ne emeexcehr at nt hi semi rsebf fye cwt sh iacnhdc tl oh fea pr aabt hi nwea, ypse nl etaods ti na tgi nt o, atno dx i c i t y ag reen ewt iecl lvuanr idaet ri os nt osoi dn , ht huemr ea ni ss lmi ma iyt ei ndf lruees ne ac er cthh ee xepf fl iocrai cnyg ahnodwt o x i c i t y owf etlhl se sa es dl i rvue gr se. nPzoyl my me so rc po hu il sdma sf f ienc tk de ry uegn az cytmi veast iloi kneadnCdKmaentda bAoDl iAs ma s, pAodtdernetsi sailnl yg at lht iesr ignagp tihnekr anpoewulteidc goeuct coouml delse aa dn dt os imd eo reef fpe cetrss.o n a l i z e d treatment approaches, improving both safety and efficacy. ● CDleoof ax ryac by itni dei na en dk iNn ea lsaer a( dbCi nKe) ai sr ec emnet rt aa bl tool i zt he edi rv itah es irma pi leaur tpi ca et hf fwi caayc sy. and exogenous toxicities. ● RG Te sPploenvseel st oi nt pr eaat itemnet sn tt ri enaTt e- Ad LwLi tcho rnr eellaatreadb iwn ei t.hTi nu tmr aocreml l uultaart iaornas- that influence ara-GTP can serve as treatment predictors. ● RtrReaMt1meexnptrreessspioonnslee.vels could also serve as a predictive marker for ● Genetic testing for polymorphisms in dCK, RRM1, ADA, CYP3A4 and pa no as sl oi bg l yt hoetrhaeprys tsoh iomu lpdr ob ve ec po na tdi eu nc tt eedx pb ee rf oi er ne cues ai nngd pt ruer ai nt me ne nu tc l e o s i d e outcomes. Conclusions

Major Take-Aways: ● Tmhoeneofpf ehcotsi vpehnoersysl aot fi ocnl obf ayrda eboi nxey cryetl ii edsi noenkiitns ai snei t(i adlC K ) a n d i t s rimetpeanitrioenffiwcaitchyi.n cells, as efflux via the ABCG2 transporter can • Th ahse br es 2e n2 9l i5n0k8e0d (t Co -v1a2r0i a5bTi)l i pt yo li yn md oC rKp ehxi spmr e isns itohne adnCdKepnrzoymmoattei cr ar ec tgiivoi nt y alonwdetrhaecvtaivriitayn.t rs2231142 in ABCG2 is a missense mutation with ● Pentostatin targets adenosine deaminase (ADA). • Genetic variants like G-to-A at position 22 (Asp8Asn) and C-to-T at pfoousnitdioinn 1A4fr5ic(aLnysA4m9eGrlnic)abnosth reduce ADA activity and are commonly . ● Ra cetdi vuacteedd ai cnttiov iittys oa cf tdi vCeK tcr ai pnhporsepvheant te Nf oerl amr a( ba irna e- Gf rToPm) , rbeedi nugc i n g therapeutic efficacy. • Vs uarrvi ai vnat ls (i rns t4h6i 9s 4e 3n 6z y2 m) aenadr er eadsus oc ec di a et ef fdi cwa ci tyh( iIn2c4rVe ,aAs e1d1 9pGr o, ga nr eds Ps i1o2n2fSr )e. e ● Sthoemiredmi-eatnabdotlriit-epshionshpibhiatteribfoornmusc.leotide reductase (RNR) via • SchoemmeoRthReMr1appyoolyumtcoormphesism leads to higher RRM1 expression and poor Table 1. CYP enzymes implicated in the metabolism of clofarabine, pentostatin, and nelarabine and their excretion. CYP enzyme Key human variants* Function CYP3A4 rs35599367 Degradation of pentostatin CYP2C8 s10509681 and rs11572080 Degradation of pentostatin and clofarabine CYP2A6 rs568811809 Degradation of pentostatin In addition to the enzymes that produce the nucleotide analogs for activity are liver enzymes that promote the degradation and excretion of these drugs.

• Antimetabolites are a diverse class of drugs that have been used extensively for chemotherapy since the 1940’s. • Antimetabolites fall into five categories based on their structural properties. They include purine analogs, pyrimidine analogs, folic acid antagonists, adenosine deaminase inhibitors, and ribonucleotide reductase inhibitors. Clofarabine, Pentostatin, and Nelarabine are relatively new purine analogs. • They disrupt the synthesis of nucleotides and substitute for purine nucleotides interfering with DNA synthesis, RNA synthesis, and ultimately functional protein production. They inhibit key enzymes critical for nucleotide biosynthesis, nucleotide salvage, and DNA repair. • The goal of this research was to provide a comprehensive overview of the key enzymes implicated in the primary and secondary metabolism of the purine nucleoside analogs clofarabine, pentostatin, and nelarabine in order to understand how they differed from other antimetabolites and to identify specific enzymes to assess to improve efficacy and minimize patient toxicity.

Methods

Records identified through database searching: PubMed (n=67) Google Scholar (n=8)

Additional articles identified through genetic variant search tool LitVar2 (n=2)

Records after duplicates removed (n=32)

Records screened based on title and abstract (n=45) Full-text articles assessed for eligibility (n=13) Articles included in analysis (n=10)

Records excluded (n=32) Full-text articles excluded for reasons: ● Ei nnczoymmpal tei tce por ro nc eo st s discussed ● Isnt uc do my oprl ecteel lmu leatra b o l i s m transport mechanism ● Up rnorceel as st eodr pnhoat rcml oasceol yl o g i c tied to pathway of study

rs1065852, rs28371706, rs59421388, rs35742686, rs769258, rs3892097, rs28371725, rs5030656 rs2069514, rs12720461, rs2069526, rs35694136

Degradation of pentostatin and clofarabine

CYP2D6

CYP1A2

Degradation of pentostatin

* Other human variants are known. Those listed have the highest population frequencies.

2025 Research Recognition Day

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