IN VIVO TOXICITY COMPARISON STUDIES BETWEEN CAMPTOTHECIN AND DISULFIDE LINKED BIOTIN CONJUGATED CAMPTOTHECIN IN COLON TUMOR BEARING RATS

Main Article Content

Amardeep Kaur
Shikha Dhiman
Manu Sharma

Keywords

Antitumor, camptothecin, conjugation, biotin, toxicity

Abstract

Camptothecin is an important chemotherapeutic agent used in the treatment of several cancers and most commonly used as first line drug in treatment of colon cancer. However, it has several side effects including nephrotoxicity, hepatotoxicity, and ototoxicity. In in vitro experiments, several vitamins have shown antitumor protective effective against toxicity produced by chemotherapeutic drugs. Biotin is one such bioactive vitamin and various authors have reported that it has strong antioxidant and antitumor potential when used in conjugation with antitumor drugs. The present study was, therefore, carried out to explore the protective potential of CPT-SS-Biotin on DMH-induced hepatotoxicity and nephrotoxicity in colon tumor-bearing rats. Animals were divided into four groups: Group I: normal control, Group II: DMH treated, Group III: DMH+ CPT-SS-Biotin treated and Group IV: DMH+ standard camptothecin. Administration of conjugated CPT significantly ameliorated the toxicity caused by DMH as indicated by improved liver function tests, kidney function tests and hematological tests more efficiently in comparison to CPT alone. The same was also evident from the improvement in the histopathological changes in kidney and testis. Blood counts were also improved on administration of conjugate to DMH-treated rats. This article provides the evidence that antioxidant efficacy of biotin has beneficial effects on DMH-induced nephrotoxicity and hepatotoxicity.

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References

1. Kratz F, Muller IA, Ryppa C, Warnecke A. Prodrug strategies in anticancer chemotherapy. ChemMedChem. 2008;3: 20−53. [CrossRef]
2. Russell-jone G, Mctavish K, Mcewan J, Rice J, Nowotnik D. Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumors. J. Inorg. Biochem. 2004;28: 1625−1633. [CrossRef]
3. Ojima I. Guided molecular missiles for tumor-targeting chemotherapy case studies using the second-generation taxoids as warheads. Acc. Chem. Res. 2008;41: 108−119. [CrossRef]
4. Chen S, Zhao X, Chen J, Kuznetsova L, Wong SS, Ojima I. Mechanism-based tumor-targeting drug delivery system. Validation of efficient vitamin receptor-mediated endocytosis and drug release. Bioconjugate Chem. 2010; 21: 979−987. [CrossRef]
5. Gupta Y, Kohli DV, Jain SK. Vitamin B12-mediated transport: a potential tool for tumor targeting of antineoplastic drugs and imaging agents. Crit. Rev. Ther. Drug Carrier Syst. 2008;25: 347−379. [CrossRef]
6. Bareford LM, Swaan PW. Endocytic mechanisms for targeted drug delivery. Adv. Drug Delivery Rev. 2007;59: 748−758. [CrossRef]
7. Xia W, Low PS. Folate-targeted therapies for cancer. J. Med. Chem. 2010;53: 6811−6824. [CrossRef]
8. Tripodo G, Mandracchia D, Collina S, Rui M, Rossi D. New Perspectives in Cancer Therapy: The Biotin-Antitumor Molecule Conjugates. Medchem, 2014;S1:004: 1-8. [CrossRef]
9. Russell-Jones G, McEwan J. Amplification of biotin-mediated targeting. Australia. Access Pharmaceuticals Australia Pty. Ltd. 2004.
10. Leamon CP, Reddy JA. Folate-targeted chemotherapy. Adv. Drug Deliv. Rev. 2004;56: 1127–1141. [CrossRef]
11. Lu Y, Low PS. Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv. Drug Deliv. Rev. 2002;54: 675–693. [CrossRef]
12. Reddy JA, Westrick E, Vlahov I, Howard SJ, Santhapuram HK, Leamon CP. Folate receptor specific anti-tumor activity of folate–mitomycin conjugates. Cancer Chemother. Pharmacol. 2006;58: 229–236. [CrossRef]
13. Leamon CP, Reddy JA, Vlahov IR, et al. Synthesis and Biological Evaluation of EC72: A New Folate-Targeted Chemotherapeutic. BioconjugateChem. 2005;16: 803–811. [CrossRef]
14. Asadi H, Khoee S. Dual responsive nanogels for intracellular doxorubicin delivery. Int. J. Pharma. 2016;511: 424–435. [CrossRef]
15. Sharma SH, Chellappan DR, Chinnaswamy P, Nagarajana S. Protective effect of p-coumaric acid against 1,2 dimethylhydrazine induced colonic preneoplastic lesions in experimental rats. Biomedicine & Pharmacotherapy. 2017;94: 577–588. [CrossRef]
16. Fadairo JK, Aladenika ST, Osaiyuwu C, Olaniyan MF, Aghatise K. Evaluation of Some Etiological Factors of Haemolytic Disease of the New Born in Ile-Ife. Open J Clin Diag. 2014; 4(1). [CrossRef]
17. Banda JM, Musa BOP, Onyemelukwe GC, Shittu SO, Babadoko AZ, Bakari AG, Mamman AI, Sarkin-Pawa A, Junaid SA . T Lymphocyte Subpopulations in Normal Pregnancies and Those Complicated by Eclampsia in Kaduna State, Nigeria . Open J Imm. 2016;6(3). [CrossRef]
18. Vagvala SH, O'Connor SD. Imaging of abnormal liver function tests. Clin Liver Dis (Hoboken). 2018 May;11(5):128-134. [CrossRef]
19. Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet. 2017;389(10075):1238–52. [CrossRef]
20. Schrier RW. Renal and electrolyte disorders: Lippincott Williams & Wilkins; 2010.
21. Ridley JW. Essential of clinical laboratory science. 1st ed. Clifton Park, NY: Delmar Cengage Learning, 2011, 457.
22. Leystra AA, Deming DA, Zahm CD, et al. Mice expressing activated PI3K rapidly develop advanced colon cancer. Cancer Research. 2012;72:2931–6. [CrossRef]