Chemosensitizing steroids: glucocorticoid receptor agonists capable of inhibiting P-glycoprotein function.
P-glycoprotein expression in lymphoid malignancies has the potential to compromise the efficacy of many therapeutic regimens using anthracyclines, glucocorticoids, and Vinca alkaloids. All three classes of drugs are transported by P-glycoproteins. We have explored the possibility that modified steroids could serve a dual purpose, as glucocorticoid receptor agonists and P-glycoprotein inhibitors. Substitution of such steroids for those currently in use would help to overcome the selective advantage held by cells expressing P-glycoproteins. 17-Deoxydexamethasone and dichlorisone were modified by the addition of a dimethylamino benzoate group at the 21-carbon atom of the steroids. The two resulting steroids, SA47 and SA450, were potent glucocorticoid receptor agonists also capable of inhibiting the human P-glycoprotein with an efficiency equal to that of verapamil. Thus, both compounds are examples of steroids that could potentially serve as beneficial substitutions for dexamethasone or prednisolone in the chemotherapy of lymphomas and leukemias.
Gruol
D J
DJ
Regulatory Biology Laboratory, The Salk Institute for Biological Studies, San Diego, California 92186-5800, USA.
Bourgeois
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000293:Adolescent; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003630:Daunorubicin / Q000378:metabolism; D003907:Dexamethasone / Q000737:chemistry / Q000378:metabolism; D005240:Feasibility Studies; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011239:Prednisolone / Q000737:chemistry / Q000378:metabolism; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011965:Receptors, Glucocorticoid; D011374:Progesterone; D003907:Dexamethasone; D011239:Prednisolone; D003630:Daunorubicin