Disease relevance of Dianhydrodulcitol

• Dianhydrogalactitol and radiation therapy. Treatment of supratentorial glioma [1].
• We conducted a prospectively randomized trial comparing whole-brain irradiation alone vs identical irradiation plus dianhydrogalactitol in 42 patients with grade 3 and 4 supratentorial astrocytomas [1].
• Dianhydrogalactitol was the most active of 177 agents tested against a mouse ependymoblastoma tumor [1].
• The DAG-induced kinetics changes were also demonstrated in a line of human adenocarcinoma of the stomach in vitro and in Ehrlich ascites tumor cells in vivo [2].
• Dibromodulcitol (DBD) and one of its most important bifunctional transformation products, dianhydrogalactitol (DAG) with similar cytostatic effect, were tested by the Salmonella/microsome assay on strains TA 1535, TA 1538, TA 98 and TA 100 using the plate incorporation technique [3].

High impact information on Dianhydrodulcitol

• The survival and cell kinetics effect of 1,2:5,6-dianhydrogalactitol, NSC-132313 (galactitol), were studied on mammalian cells [4].
• The pharmacokinetics of dianhydrogalactitol (DAG), NSC-132313, were studied in the beagle dog at doses of 3 mg - kg-1 and 6 mg - kg-1 [5].
• This blockade in S phase was reversible and was followed at 18 hr after an exposure to DAG by a 200% increase in the fraction of cells in the G2-M phases of the cell cycle [2].
• Alkylation by 1,2:5,6-dianhydrogalactitol of deoxyribonucleic acid and guanosine [6].
• In dose-response experiments, P1 and P4 clones were more sensitive to dianhydrodulcitol than tp0 or P3 clones [7].

Chemical compound and disease context of Dianhydrodulcitol

• In a phase I study, a monthly regimen of dianhydrogalactitol 60 mg/m2 X 1 day, VP-16-213 60 mg/m2 X 3 days, and cis-platinum 20 mg/m2 X 3 days produced clinically acceptable toxicity [8].
• Apart from cyclophosphamide, which is known to have activity against lymphoma and was used as a positive control, only dianhydrogalactitol (DAG) had antitumor activity in the lymphoma-bearing nude mice [9].
• Cultured P388/S mouse lymphoma cells resistant to 5-bromodeoxyuridine (BUdR) and deficient in thymidine kinase (TK-) were fused with P388/DAG cells resistant to 1,2:5,6-dianhydrogalactitol (DAG), an anticancer alkylating agent, and to 6-thioguanine (6-TG) and deficient in hypoxanthine phosphoribosyl-transferase (HPRT-) [10].
• Human meningeal sarcoma heterotransplants in Nu/Nu mice treated with L-phenylalanine mustard (L-PAM) and dianhydrogalactitol (DAG) [11].
• Combination carmustine (BCNU) and dianhydrogalactitol in the treatment of primary brain tumors recurring after irradiation [12].

Biological context of Dianhydrodulcitol

• Cell killing, kinetics, and recovery responses induced by 1,2:5,6-dianhydrogalactitol in dividing and nondividiing cells in vitro [4].
• Bromoepoxydulcitol (BED), dianhydrodulcitol (DAD) are cytotoxic, whereas bromoanhydrodulcitol (BAD) and anhydroepoxydulcitol (AED) are inactive metabolites detectable during the biotransformation of DBD [13].
• Bacterial translocation in dianhydrodulcitol-treated mice [14].
• Although GCE effectively inhibits cell proliferation, its single dose does not induce such toxic, irreversible and degenerative ultrastructural alterations as have been observed in the same system after the administration of the cytostatic dianhydrogalactitol [15].
• Clone 6 cells were polyploid and more sensitive to dianhydrogalactitol than the diploid clone 10 cells [16].

Anatomical context of Dianhydrodulcitol

• In an on-going Phase II evaluation, dianhydrogalactitol (NSC 132313) was administered intravenously to 28 patients with advanced or recurrent non-squamous cell carcinoma of the cervix [17].
• Effect of a single high dose and repeated small doses of dianhydrogalactitol (DAG; NSC-132313) on rat intestinal mucosa [18].
• Dianhydrogalactitol (DAG) or its active cell-killing moiety has a relatively long biological half-life in 9L cells cultured in vitro [19].
• Cytokinetics of a human neuroblastoma cell line following treatment with dianhydrogalactitol [20].
• Both DAG and Diac-DAG inhibited the enzyme activities of the proliferating and mature enterocytes in a dose dependent fashion, primarily acting on the crypt specific thymidine kinase [21].

Associations of Dianhydrodulcitol with other chemical compounds

• Three hexitol derivatives, dibromomannitol (DBM), dibromodulcitol (DBD), and dianhydrogalactitol (DAG), originally investigated in Hungary, have been evaluated as anticancer agents in the United States. Their principal mechanism of action is attributed to alkylation via actual or derived epoxide groups [22].
• When this is achieved, the patient is treated with maximal therapy, i.e., total body irradiation, high-dose L-phenylalanine mustard and dianhydrogalactitol followed by reconstitution with an autologous bone marrow graft [23].
• Like LAK, both HAK and D-LAK were able to compensate for the immunosuppressive effect of the cytotoxic drugs dianhydrogalactitol, vincristine, and 5-fluorouracil, which all have different mechanisms of action, provided that combined treatment by polypeptide and drug was applied repeatedly before the SRBC immunization [24].

Gene context of Dianhydrodulcitol

• The same dose of dianhydrodulcitol (DAD) produced a lower mortality rate among germfree mice than among SPF or conventional C3H mice [25].
• We conclude that the addition of substantial and toxic doses of dianhydrogalactitol to DDP failed to substantially enhance the rate, quality, or duration of response compared to DDP alone [26].

Analytical, diagnostic and therapeutic context of Dianhydrodulcitol

• Use of 1,2:5,6-dianhydrogalactitol in studies on cell kinetics-directed chemotherapy schedules in human tumors in vivo [27].
• Rapid analysis by flow microfluorometry techniques was used to determine the DAG-induced kinetics changes, thus allowing treatment with the second drugs at the most opportune time [2].
• This effect can be attributed to the presence of DAG and EAD which could be identified by thin-layer chromatography of urine, thus establishing the premutagenic character of DisuDAG [28].
• Ten hr after treatment with 1,2:5,6-dianhydrogalactitol (DAG) (at a dose lethal to less than 5% of the cells), a 150% enrichment of cells into the S phase of the cell cycle was observed [2].
• Practicality of the method for monitoring drug distribution was demonstrated by administering dianhydrogalactitol in therapeutic doses to a dog and monitoring its concentrations in blood for the next 2 h [29].

References