EXPLORING THE INTRAVENOUS COMBINATION OF D-ISOASCORBIC ACID (D-VC) AND ARSENIC TRIOXIDE IN ADVANCED/METASTATIC MALIGNANCIES
Main Article Content
Authors
B.A.
Yermekbayeva
National Laboratory Astana, Astana, the Republic of Kazakhstan
U.Y.
Kairov
National Laboratory Astana, Astana, the Republic of Kazakhstan
D.A.
Begimbetova
National Laboratory Astana, Astana, the Republic of Kazakhstan
A.M. Kukanova
National Laboratory Astana, Astana, the Republic of Kazakhstan
Astana Medical University, Astana, the Republic of Kazakhstan;
A.K.
Makishev
Astana Medical University, Astana, the Republic of Kazakhstan;
Abstract
Background: Addressing the therapeutic challenges associated with Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) mutant cancers remains a significant focus in oncology. The combined intravenous administration of the D-isomer of vitamin C (D-VC) (dextro-rotatory isomer of ascorbic acid) and arsenic trioxide (ATO) is proposed as a potential approach for achieving an anti-tumor effect in Colorectal cancer (CRC) with KRAS-mutant tumor cells. ATO enhances the oxidative effect of vitamin C (VC), and the combination of both drugs provides effective eradication of KRAS-mutant cancer cells. A potent synergistic effect of the VC and ATO combination has been observed about KRAS-mutant cancer cells.
Purpose: This clinical trial aims to assess the tolerability and safety of intravenous administration of D-VC along with ATO in patients with advanced/metastatic malignancies who have exhausted standard therapy.
Methods and Patients: This single-center Phase I clinical trial evaluated the tolerability and safety of D-VC when administered intravenously alone or in sequential administration with ATO. The target group for the Phase I exploratory clinical trial includes 10 patients with advanced/metastatic malignant neoplasms who have exhausted standard therapy.
Results: The administration of the drug followed the treatment regimen according to the ap-proved study protocol. After a single intravenous infusion of D-VC in escalating doses of 0.05 g/kg - 0.1 g/kg - 0.15 g/kg - 0.3 g/kg all patients felt satisfactory, and no subjective intolerance to the investigational drug was reported. The main functional and laboratory parameters remained within normal values recorded at the start of the study. The maximum tolerated dose of D-VC was determined to be 0.3 g/kg, and this dose was chosen as the baseline for the second stage of the study, where D-VC (0.3 g/kg) was administered alongside ATO (0.15 mg/kg).
Conclusions: Our findings showed favorable safety and well-tolerated profiles and provided the recommended dose for high-dose D-VC in combination with АТО.
Keywords
Cancer, KRAS, arsenic trioxide (ATO), vitamin C enantiomer D (D-VC), Phase I and Phase II clinical trials
Article Details
References
Palmeira CM, Teodoro JS, Amorim JA, Steegborn C, Sinclair DA, Rolo AP. Mitohormesis and metabolic health: The interplay between ROS, cAMP and sirtuins. Vol. 141, Free Radical Biology and Medicine. Elsevier Inc.; 2019. p. 483–91.
Hunyady J. The Result of Vitamin C Treatment of Patients with Cancer: Conditions Influencing the Effectiveness. Vol. 23, International Journal of Molecular Sciences. MDPI; 2022.
Cenigaonandia-Campillo A, Serna-Blasco R, Gómez-Ocabo L, et al. Vitamin C activates pyruvate dehydrogenase (PDH) targeting the mitochondrial tricarboxylic acid (TCA) cycle in hypoxic KRAS mutant colon cancer. Theranostics. 2021;11(8):3595–606.
Wu X, Park M, Sarbassova DA, et al. A chirality-dependent action of vitamin C in suppressing Kirsten rat sarcoma mutant tumor growth by the oxidative combination: Rationale for cancer therapeutics. Int J Cancer [Internet]. 2020 May 15;146(10):2822–8. Available from: Crossref
Zinovkin RA, Lyamzaev KG, Chernyak B V. Current perspectives of mitochondria-targeted antioxidants in cancer prevention and treatment. Front Cell Dev Biol. 2023 Mar 16;11
Lee SS, Choi SJ, Park JS. Correlations among KRAS Mutation, Microsatellite Instability, and 18F-FDG Uptake in Colon Cancer. Asian Pacific J Cancer Prev. 2022;23(10):3501–6.
Begimbetova D, Kukanova A, Fazyl F, et al. The Oxidative Drug Combination for Suppressing KRAS G12D Inducible Tumour Growth. Husain K, editor. Biomed Res Int [Internet]. 2022; 2022:9426623. Available from: Crossref
Subbarayan P, Ardalan B. (2014). In the War Against Solid Tumors Arsenic Trioxide Need Partners. Journal of Gastrointestinal Cancer, 45(3), 363–371. doi:10.1007/s12029-014-9617-8.
Wu X, Park M, Sarbassova D, et al. A chirality-dependent action of vitamin C in suppressing Kirsten rat sarcoma mutant tumor growth by the oxidative combination: Rationale for cancer therapeutics. Int. J Cancer 2020, 146, 2822–2828].
van Gorkom GNY, Lookermans EL, Van Elssen C, Bos GMJ. The effect of vitamin C (ascorbic acid) in the treatment of patients with cancer: a systematic review. Nutrients 2019; 11:977.
Wang F, He MM, Xiao J, et al. A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vita-min C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Un-treated Metastatic Colorectal Cancer (VITALITY Study). Clin Cancer Res. 2022 Oct 3;28(19):4232-4239.
Shekunova E V., Kovaleva MA, Makarova MN, Makarov VG. Dose Selection in Preclinical Studies: Cross-Species Dose Conversion. Bull Sci Cent Expert Eval Med Prod. 2020 Feb 26;10(1):19–28.
Nair A, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27.
Li ZN, Zhao L, Yu LF, Wei MJ. BRAF and KRAS mutations in metastatic colorectal cancer: Future perspectives for personalized therapy. Vol. 8, Gastroenterology Report. Oxford University Press; 2020. p. 192–205.
Zasowska-Nowak A, Nowak PJ, Ciałkowska-Rysz A. High-dose vitamin c in advanced-stage cancer patients. Vol. 13, Nutrients. MDPI AG; 2021. p. 1–29.
Mussa A, Mohd Idris RA, Ahmed N, et al. High-Dose Vitamin C for Cancer Therapy. Vol. 15, Pharmaceuticals. MDPI; 2022.
Roy S, Chourasia P, Sangani V, Errabelli PK, Patel SS, Adapa S. Megadose Vitamin C Prescription Through Alternative Medicine Leading to End-Stage Renal Disease: Case Study and Literature Review. J Investig Med High Impact Case Reports. 2023 Jan;11:232470962311589.
Padayatty SJ, Sun H, Wang Y, et al. Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use. Ann Intern Med. 2004 Apr 7;140(7).
Qin S, Wang G, Chen L, et al. Pharmacological vitamin C inhibits mTOR signaling and tumor growth by degrading Rictor and inducing HMOX1 expression. PLoS Genet. 2023 Feb 14;19(2).
Jovičić MŠ, Pušić M, Antunović M, et al. effects of ascorbic acid on viability and metabolism of patients’ osteosarcoma stem cells. Acta Pharm [Internet]. 2022;72(4):599–613. Available from: Crossref
Doseděl M, Jirkovský E, Macáková K, et al. Vitamin c—sources, physiological role, kinetics, deficiency, use, toxicity, and determination. Vol. 13, Nutrients. MDPI AG; 2021. p. 1–36.
On approval of the rules for conducting preclinical (nonclinical) studies and requirements for preclinical bases for assessing the biological effect of medical devices. Order of the Minister of Health of the Republic of Kazakhstan dated December 11, 2020 No. ҚР ДСМ-255/2020. Registered with the Ministry of Justice of the Republic of Kazakhstan on December 15, 2020 No. 21794. 2020.