Mechanism of action of oxazaphosphorine cytostatics and anti metastatic experimental therapy with SUMIAP a new Ifosfamide derivative adapted

Research Article


Abstract views: 45 / PDF downloads: 26

Authors

  • Georg Voelcker

DOI:

https://doi.org/10.58372/2835-6276.1027

Keywords:

Mechanism of action of oxazaphosphorine cytostatics, Aldophosphamide-perhydrothiazines, SUM-IAP, anti metastatic therapy, N-methylformamide, Immunstimulation by SUM-IAP

Abstract

SUM-IAP is an Ifosfamide derivative adapted to the mechanism of action of Ifosfamide (IF). IF and other oxazaphosphorines (OX) are hydroxylated in the liver by cytochrome P450 enzymes. The formed 4-hydroxy-oxazaphosphorine (OXOH) forms an equilibrium mixture with its tautomer OX-aldophosphamide (OXALD). OXALD is the pharmacologically active metabolite from which the two therapeutically active metabolites OX-phosphoreamidemustard (OXPAM) and 3-hydroxypropanal (HPA) are formed by enzymatic cleavage with esterases. OXPAM damages the DNA by alkylation and thus initiates apoptosis like other alkylating substances. What is special about OX, however, is that alkylation-initiated apoptosis is enhanced by the pro apoptotic HPA. Now OX were found by a happy coincidence and were not tailor-made for the mechanism of action described, so that the therapeutic possibilities hidden in the mechanism of action are not fully exploited.

SUM-IAP is a new developed substance tailored to the mechanism of action. Chemically speaking, SUM-IAP is the I-aldophosphamide-perhydrothiazine with a modified alkylating function. In contrast to the alkylating function of IF, the modified alkylating function of SUM-IAP generates DNA intra strand crosslinks that are difficult or impossible to repair by cellular repair, thereby increasing the apoptosis yield compared to IF, which generates easily repairable inter strand crosslinks. With I-aldophosphamide-perhydrothiazne (IAP) containing the alkylating function of IF and with SUM-IAP, therapy experiments with P388 tumor bearing CD2F1mice were carried out. It is shown that SUM-IAP the alkylating function of which is adapted to the mechanism of action of OX, is in vivo orders of magnitude more effective than IAP.

Therapy experiments with SUM-IAP and CD2F1 mice bearing subcutaneously transplanted P388 tumors showed that although the transplanted primary tumor is eradicated, the mice die from SUM-IAP-resistant metastases between days 40 and 70 after tumor transplantation. The following article describes experiments demonstrating the mechanism of action of OX and experiments to prevent metastasis formation.

References

Tomitka, K.; Takeuchi, T. On the phosphamidase reaction of tumor tissues. Gann 1955, 46, 333–334.

Brock, N.; Hohorst, H.J. The problem of specificity and selectivity of alkylating cytostatics: Studies on N-2-chlorethylamido oxazaphosphorines. Z. Krebsforsch 1977, 88, 185–215.

Voelcker, G. Enzyme Catalyzed Decomposition of 4-Hydroxycyclophosphamide. Open Conf. Proceeding J.2017, 8, 44–51.

Iyer, C.; Kosters, A.; Sethi, G.; Kunnumakkara, A.B.; Aggarwal, B.B.; Versalovic, J. Probiotic Lactobacillus reuteri promotes TNF-induced apoptosis in human myeloid leukemia-derived cells by modulation of NF-kappaB and MAPK signalling. Cell. Microbiol. 2008, 10, 1442–1452.

Schwartz, P.S.;Waxman, D.J. Cyclophosphamide induces caspase 9-dependent apoptosis in 9L tumor cells. Mol. Pharmacol. 2001, 60, 1268–1279.

Voelcker, G. Haeglsperger, R. Pharmacokinetics of cyclophosphamide and cyclophosphamide metabolites in the mouse and their influence on the therapeutic effect of “activated” cyclophosphamide (4-hydroxycyclophosphamide) (author’s transl). Arzneimittelforschung 1982, 32, 639–647.

Seki, K.; Yoshikawa, H.; Shiiki, K.; Hamada, Y.; Akamatsu, N.; Tasaka, K. Cisplatin (CDDP) specifically induces apoptosis via sequential activation of caspase-8, -3 and -6 in osteosarcoma. Cancer Chemother harmacol., 2000, 45(3), 199-206.

Matz EL, Hsieh MH. Review of advances in uroprotective agents for cyclophosphamide- and ifosfamide- induced hemorrhagic cystitis. Urology 2017; 100:16–19.

Wagner T. Ifosfamide, Clin Pharmacokinet 1994 Jun;26(6):439-56.

Voelcker G Causes and possibilities to circumvent cyclophosphamideToxicity Anti-Cancer Drugs 2020, 31:617–622

Voelcker G, Pfeiffer B, Schnee A, Hohorst H.J. Increased antitumour activity of mesyl-I-aldophosphamide-perhydrothiazine, in vivo but not in vitro, compared to I-aldophosphamide-perhydrothiazine. Cancer Res Clin Oncol. 2000 Feb;126(2):74-8.

Voelcker G. Future perspective of oxazaphosphorine cytostatics, Trends in Cancer Research 18,27-37 2021.

Alexander P, Mikulski Z. Differences of response of leukemia cells in tissue culture to nitrogen mustard and to dimethyl-myleran. Biochem Pharmacol 1961; 5:275–282.

Heylmann D, Bauer M, Becker H, van Gool S, Bacher N, Steinbrink K, Kaina B. Human CD4+CD25+ regulatory T cells are sensitive to low dose cyclophosphamide: implications for the immune response. PLoS One 2013; 8:12.

Clarke CA, Philips SF, Sternber SS (1953) Effects of N-methylformamide and related compounds in sarcoma 180. Proc Soc Exp Biol Med 84:203–207.

Kalyani D, Jyothi K, Sivaprakasam C, Nachiappan V (2014) Spectroscopic and molecular modeling studies on interactions of N-methylformamide with superoxide dismutase. Mol Biomol Spectrosc 124:148–152.

Iwakawa M, Tofilon PJ, Hunter N, Stephens LC, Milas L (1987) Antitumor and antimetastatic activity of the differentiating agent N-methylformamide in murine tumor systems. clin Exp Metastasis.

Voelcker G. Enhancement of antitumor activity of the oxazaphosphorine cytostatic SUM IAP by N methylformamide G. Voelcker J Cancer Res Clin Oncol.

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Published

2023-02-28

How to Cite

Georg Voelcker. (2023). Mechanism of action of oxazaphosphorine cytostatics and anti metastatic experimental therapy with SUMIAP a new Ifosfamide derivative adapted: Research Article. American Journal of Medical and Clinical Research & Reviews, 2(2), 1–12. https://doi.org/10.58372/2835-6276.1027

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