Evaluation of dimethylaminosulfonates of alkane diols as a novel group of anticancer agents.
A series of title compounds has been synthesized and evaluated by the cytotoxicity assays conducted in vitro in seven human tumor cell lines, initially in MT-4 and H-9, followed by U-937, PM-1, MCF-7, Hep-3B, and K-562. These compounds were simultaneously compared with the existing clinical drug, busulfan and also with an experimental drug, hepsulfam. IC(50) values of these agents in T-cell lymphoma and leukemic cell lines indicate that two of these agents hexsulfamyl and octsulfamyl (compounds 3 and 4) were significantly more potent than busulfan and were comparable in antileukemic activity with hepsulfam. In order to determine the effect of these agents on normal proliferating cells, the toxicity of 3 and 4 was also determined in vitro against human peripheral blood mononuclear cells (PBMC) and against murine bone marrow progenitor cells. PBMC assay data indicate that these agents were generally less toxic than hepsulfam. The results of the colony forming unit-erythroid (CFU-E) and granulocyte-macrophage colony forming unit (CFU-GM) assays, however, indicate that these agents were more toxic than hepsulfam to erythroid progenitor cells than to granulocyte-macrophage progenitors. The toxicity of octsulfamyl was further assessed in vivo in normal Swiss mice by measuring drug-induced changes in hematological parameters, femoral bone marrow cellularity and splenic cellularity as well as hepatotoxicity and nephrotoxicity on day 7 and 14 following drug treatment at the dose of 1.0 mg/kg body weight from days 1 to 5. The results indicate that the compound did not adversely affect hematopoiesis. Marginal bone marrow suppression was observed on day 7, which gradually tends to reach normalcy on day 14. The other parameters were within normal limit.
Sanyal
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Department of Anticancer Drug Development and Chemotherapy, Chittaranjan National Cancer Institute, Calcutta, India. cncinst@giasc101.vsnl.net.in
Nanda
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Samanta
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Pain
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Dutta
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Verma
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Rider
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BJ
Agrawal
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KC
D000473:Alkanes / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects; D002066:Busulfan / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D006098:Granulocytes / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008698:Mesylates / Q000494:pharmacology*; D051379:Mice; D013450:Sulfones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000473:Alkanes; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D008698:Mesylates; D013450:Sulfones; D002066:Busulfan