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

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.