INHIBITION OF HUMAN CLASS-3 ALDEHYDE DEHYDROGENASE, AND SENSITIZATIONOF TUMOR-CELLS THAT EXPRESS SIGNIFICANT AMOUNTS OF THIS ENZYME TO OXAZAPHOSPHORINES, BY CHLORPROPAMIDE ANALOGS

In some cases, acquired as well as constitutive tumor cell resistance to a group of otherwise clinically useful antineoplastic agents collec tively referred to as oxazaphosphorines, e.g. cyclophosphamide and maf osfamide, can be accounted for by relatively elevated cellular levels of an enzyme, viz. cytosolic class 3 aldehyde dehydrogenase (ALDH-3), that catalyzes their detoxification. Ergo, inhibitors of ALDH-3 could be of clinical value since their inclusion in the therapeutic protocol would be expected to sensitize such cells to these agents. Identified in the present investigation were two chlorpropamide analogues showin g promise in that regard, viz. (acetyloxy)[(4-chlorophenyl)sulfonyl]ca rbamic acid 1,1-dimethylethyl ester (NPI-2) and ethoxy-N-[(propylamino )carbonyl]benzenesulfonamide (API-2). Each inhibited NAD-linked benzal dehyde oxidation catalyzed by ALDH-3s purified from human breast adeno carcinoma MCF-7/0/CAT cells (IC50 values were 16 and 0.75 mu M, respec tively) and human normal stomach mucosa (IC50 values were 202 and 5 mu M, respectively). The differential sensitivities of stomach mucosa AL DH-3 and breast tumor ALDH 3 to each of the two inhibitors can be view ed as further evidence that the latter is a subtle variant of the form er. Human class 1 (ALDH-1) and class 2 (ALDH-2) aldehyde dehydrogenase s were much less sensitive to NPI-2; IC50 values were >300 mu M in eac h case. API-2, however, did not exhibit a similar degree of specificit y; IC50 values for ALDH-1 and ALDH-2 were 7.5 and 0.08 mu M, respectiv ely. Each sensitized MCF-7/0/CAT cells to mafosfamide; the IC50 value decreased from >2 mM to 175 and 200 mu M, respectively. Thus, the ther apeutic potential of combining NPI-2 or API-2 with oxazaphosphorines i s established. (C) 1998 Elsevier Science Inc.