Add time:07/31/2019         Source:sciencedirect.com

SummaryThis article has surveyed the current status of dibromodulcitol with respect to chemistry, mechanism of action, animal and human pharmacology and experimental and clinical antitumor activity. The following conclusions may be drawn:(1)As an alpha, omega dibrominated hexitol, DBD shares many of the biochemical and biological properties of similar drugs such as dibromomannitol and mannitol myleran.(2)Activation of DBD to the diepoxide DAG occurs in vivo, and the latter probably represents a major active form of the drug.(3)Present evidence indicates that DAG acts as a bifunctional alkylating agent, producing covalent cross-linking between DNA strands. Interaction with histone protein of chromatin may contribute significantly to its cytotoxic action.(4)Absorption of DBD by the oral route is rapid and fairly complete.(5)Distribution of DBD is rapid and extensive, and the drug is bound to serum albumin in an intact form which seems to be protected from cleavage of the carbon-bromine bonds. DBD enters CSF and third space compartments readily, and the latter may influence its overall clearance rate from plasma.(6)Metabolism of DBD to monobrominated metabolites and to DAG is extensive and rapid.(7)Excretion of DBD and metabolites is predominantly renal, although high levels of drug are found in bile and small intestine. This implies significant enterohepatic circulation.(8)Dose-limiting toxicity of DBD in animals and man is myclosuppression, which is dose-related and may be prolonged following periods of daily administration.(9)Minor toxicities of DBD include nausea and vomiting, anorexia, diarrhea, dyspnea, abnormal liver function tests, skin pigmentation, pruritis, vertigo, azotemia, alopecia, dysuria, allergic reactions and local tumor pain and hemorrhage.(10)Effective dosage regimens include:(a)2.5 to 3.5 mg/kg/day for 5–7 weeks per os.(b)4–5 mg/kg/day for 10–20 days per os, repeated monthly.(11)Cross-resistance to other alkylating agents is incomplete in the clinical setting, implying a role for DBD in second-line therapy following regimens containing an alkylating agent.(12)Synergism between DBD and cyclophosphamide, 5-fluorouracil, adriamycin and BCNU may occur.(13)The spectrum of activity shown by DBD in animal tumors is wide, implying good potential for clinical activity. There may be an antimetastatic effect similar to that of 5-fluorouracil and ICRF-159.(14)Clinical activity of DBD against breast carcinoma, head and neck carcinoma, lymphomas and melanoma has been confirmed. Suggestions of activity in pulmonary, gastric, renal, ovarian, uterine, colonic and bladder carcinomas, as well as in brain tumors and sarcomas, have been noted.(15)Combination regimens incorporating DBD have produced good results in breast carcinoma, non-small cell lung cancer and remission maintenance in acute pediatric leukemia, with probable decrease in the incidence of CNS recurrence in the last disease.(16)The role of DBD in combination chemotherapy and combined modality approaches to human cancer is underdeveloped at this time. DBD will probably become an important addition to the pharmacological armamentarium of the clinical oncologist.

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