Absence of cross-resistance between two alkylating agents: BCNU vs bifunctional galactitol

Abstract

Dianhydrogalactitol (DAG) increased the life span of both BCNU-sensitive and -resistant L1210 tumor-bearing mice. However, the BCNU-resistant strain showed slightly lower sensitivity against DAG, which could be overcome by an increase in drug dose of ca. 20%. The somewhat lower sensitivity was proportional to a slightly reduced DNA cross-linking formation induced by DAG in BCNU-resistant cells. The amount of DNA cross-links was determined by measurement of the 1,6-di(guaninyl)-galactitol content of DNA. The slight reduction in cross-links is not attributable to DNA repair but rather to other factors that seem to prevent the formation of DNA-drug adducts. The absence of cross-resistance is explained by different kinds of DNA damage caused by the two alkylating agents and the presumably different defense mechanisms developed by cells against these lesions.

Dianhydrogalactitol induces replication-dependent DNA damage in tumor cells preferentially resolved by homologous recombination

“…Many chemotherapeutic drugs work by inducing different types of DNA damage in rapid-dividing cancer cells. DAG has been reported to have bifunctional DNA-targeting activity leading to the formation of N 7 -monoalkylguanine and inter-strand DNA crosslinks 22 . To investigate the effects of DAG on DNA integrity, we examined VAL-083-treated NSCLC cells for phosphorylated histone variant H2AX (ɣH2AX), an extensively used surrogate marker of DNA double-strand breaks (DSBs) 23 , 24 .…”

“…However, despite encouraging preclinical and clinical data in NSCLC and GBM, timely advancement of DAG analogs toward the clinical arena is hampered by inadequate understanding of the molecular mechanisms responsible for DAG-mediated cytotoxicity in cancer cells. We therefore used NSCLC as a model system to investigate the mechanisms of cytotoxicity imposed by the clinical-grade DAG analog VAL-083 22 .…”

Synthesis and structure of selected quaternary N-(1,4-anhydro-5-deoxy-2,3-O-isopropylidene-d,l-ribitol-5-yl)ammonium salts

“…The rate of formation of the quaternary ammonium salts of aromatic amines is affected by electronic effects, as seen in the 45% yield of the N-(1,4-anhydro-5-deoxy-2,3-O-isopropylidene-D D,L L-ribitol-5-yl)-3-carbamoylpyridinium tosylate (8). In this case the yield is rather low in spite of absence of the steric hindrance.…”

“…4198 (15) 3816 (13) 10305 (4) 108(4) C (2) 3723 (10) 3362 (9) 9793 (3) 63 (2) C(3) 4272 (12) 2086 (10) 9609 (3) 73 (3) C(4) 3868 (10) 1658 (10) 9145 (3) 62(2) C (5) 2855 (10) 2465 (8) 8855 (2) 45(2) C (6) 2306 (11) 3738 (8) 9024 (3) 57(2) C (7) 2757 (12) 4145 (9) 9493 (3) 69(2) C (8) À2450 (20) 5158 (14) 9309 (4) 132 (5) C(9) À2392 (12) 6562 (9) 9052 (3) 69 (2) C(10) À3948 (17) 7373 (15) 9096 (5) 127 (5) C(11) À337 (11) 8158 (10) 8863 (3) 65(2) C (12) 1484 (11) 7997(10) 8874 (3) 66 (2) O(6) 1827 (7) 6803 (7) 8572 (2) 68 (2) C(14...…”

“…7 Both animal and preliminary clinical tests have shown that 1,2:5,6-dianhydrogalactitol (DAG) is an effective drug for the treatment of some tumors, for instance those of the lung and brain, as well as leukemia. 8 Both chemists and biologists are currently interested in pseudo-nucleosides in which the sugar residue is substituted by 1,4-anhydropentitol or 1,5-anhydrohexitol derivatives. Some of these compounds are effective against viruses, for instance against the HIV virus.…”