Cyclophosphamide potentiation and aldehyde oxidase inhibition by phosphorylated aldehydes and acetals

Abstract

Fourteen phosphorylated acetals and aldehydes were synthesized for testing in vitro as inhibitors or substrates of aldehyde oxidase, an enzyme involved in the conversion of aldophosphamide to inactive carboxyphosphamide, and for concurrent in vivo administration with cyclophosphamide to mice bearing L1210 ascites tumor cells. Five phosphorus derivatives gave Ki values of 0.1--0.3 mM compared to 0.03 mM for pyridoxal, as determined in aldehyde oxidase assays using N-methylnicotinamide as the substrate. The most active phosphorus inhibitor, ethyl phenyl(2-formylethyl)phosphinate (2b), and pyridoxal were further shown to give competitive and mixed inhibition, respectively. Three aldehydes, administered concurrently with cyclophosphamide, produced greater increases in life span of L1210-implanted mice than did pyridoxal. All four agents gave an average increase in life span greater than 50% over that shown by cyclophosphamide alone.

Cloning of the cDNAs Coding for Two Novel Molybdo-flavoproteins Showing High Similarity with Aldehyde Oxidase and Xanthine Oxidoreductase

“…3 Thus, it is possible that AOH2 plays a role in the process of homeostasis and/or differentiation of the keratinocyte and the squamous epithelial cell in more general terms. With respect to this, it could be speculated that, as already suggested for AO (32), AOH2 also has a role in the metabolism of natural retinoids, which are well known determinants of the differentiation state of the keratinocyte (56).…”

“…AO is much less studied, and a physiological substrate for the enzyme has not yet been established, although there are reports indicating that the enzyme oxidizes retinaldehyde into retinoic acid (29) and is involved in the catabolism of the monoamine neurotransmitters (30). Moreover, the AO protein is of considerable pharmacological and toxicological importance, given its role in the metabolism of drugs such as methotrexate (31) and cyclophosphamide (32). Finally, the AO gene has been recently implicated in the etiopathogenesis of the familial recessive form of amyotrophic lateral sclerosis, a rare motor neuron disease (33).…”

The mammalian aldehyde oxidase gene family

“…Extensive discussion of the compounds metabolised by human or rodent aldehyde oxidases is beyond the scope of this paper, and the reader is referred to specific reviews for more details [34,40,41]. It is worth mentioning that aldehyde oxidases have an important role in the metabolism of the anti-tumour and immunosuppressive agents, methotrexate,[42] 6-mercaptopurine and azathioprine,[43,44] and aldophosphamide, the active metabolite of cyclophosphamide [45,46]. Aldehyde oxidases have also been reported to metabolise the antimalarial agent, quinine [47] and the anti-viral drug famcyclovir [48].…”

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

“…Inhibition of ALDH1A expression by antisense RNA sensitizes tumor cells to 4-OH- CPA in vitro [429]. The known inhibitors of ALDH, disulfiram, diethyldithiocarbamate, and cyanamide partially restored the sensitivity of these resistance cells to CPA, 4-OH-CPA and other oxazaphosphorines [427,430,431]. Retinoic acid [a substrate for ALDH [432]] down-regulated ALDH1A1 and 3A1 enzyme activity and increased cytotoxicity of 4-OH-CPA and acetaldehyde in A549 and other lung cancer cell lines [89].…”