mesna and Leukemia-P388

5'-[4-(Pivaloyloxy)-1,3,2-dioxaphosphorinan-2-yl]-2'-deoxy-5 -fluorouridine (1c) was designed as a potential membrane-permeable prodrug of 2'-deoxy-5-fluorouridine 5'-monophosphate (FdUMP), a putative active metabolite of the antitumor drug 5-fluorouracil (FU). It was anticipated that 1c would be hydrolyzed in vivo by carboxylate esterase (E.C. 3.1.1.1) to the labile 4-hydroxy analogue 2a, which should penetrate cells by passive diffusion and ring open to the aldehyde 3a. Spontaneous elimination of acrolein from 3a would then generate the free nucleotide, FdUMP. 1c might also penetrate cells directly and undergo the same degradation sequence after hydrolysis by cellular esterases. 1c was prepared by condensing 2-hydroxy-2-oxo-4-(pivaloyloxy)-1,3,2-dioxaphosphorinane with 2'-deoxy-5-fluorouridine (FUdR) in the presence of triphenylphosphine and diethyl azodicarboxylate. 1c was moderately stable in aqueous buffers over the pH range 1-7.4 (T1/2 > 30 h). In the presence of carboxylate esterase, however, it was degraded, in a concentration-dependent manner, to FdUMP. No intermediates were detected in the incubation mixture. In mouse plasma, 1c was degraded first to FdUMP and then to FUdR. The latter is presumably formed by dephosphorylation of FdUMP by plasma 5'-nucleotidases or phosphatases. 1c and FU inhibited the growth of Chinese hamster ovary (CHO) cells in culture at a concentration of 5 x 10(-6) M. 1c was equally potent against a CHO variant that was 20-fold resistant to FU. Administered intraperitoneally for 5 consecutive days, 1c was as effective as FU at prolonging the life span of mice bearing P-388 leukemia. In the presence of 2-mercaptoehtanesulfonic acid, an acrolein scavenger, 1c was equally effective against a P-388 mutant cell line that was resistant to FU. Collectively, these data suggest that 1c acts as a membrane-permeable prodrug of FdUMP. This prodrug strategy may be generally useful for introducing dianionic phosphates and phosphonates into cells.

Topics: Animals; Antimetabolites, Antineoplastic; Cell Division; Cell Membrane; CHO Cells; Cricetinae; Esterases; Fluorodeoxyuridylate; Leukemia P388; Male; Mice; Phosphoric Monoester Hydrolases; Prodrugs; Swine

Reaction of 1-(4-bromophenyl)-4,4-dimethyl-5-(1-piperidino)-1-penten-3-one hydrochloride (1f) with sodium 2-mercaptoethanesulphonate (mesna) gave rise to the thiol adduct. 3. Recrystallization of this compound led to the formation of the corresponding zwitterion 4f. A series of analogues of 4f were prepared and the structure of a representative compound was confirmed by X-ray crystallography. In general, the thiol adducts had similar activity towards P388 cells and human tumour cell lines as the precursor enones 1 although greater selectivity to malignant diseases was found with the thiol adducts. A stability study of representative compounds conducted by 1H NMR spectroscopy revealed that the thiol adducts decomposed in solution. In one case regeneration of the ketone was noted while for the other compounds, the decomposition products were not identified.

Topics: Animals; Antineoplastic Agents; Crystallography, X-Ray; Humans; Ketones; Leukemia P388; Magnetic Resonance Spectroscopy; Mannich Bases; Melphalan; Mesna; Mice; Molecular Conformation; Piperidines; Tumor Cells, Cultured

The uroprotectant thiol mesna was found to protect adult CD-1 mice from high-dose cisplatin lethality. Mesna doses of 50 mg/kg were given with cisplatin, or 5 min after cisplatin (25 or 30 mg/kg) and acute survival was increased in non-tumor-bearing mice. In contrast, mesna mixed directly with cisplatin significantly reduced cisplatin antitumor effects in DBA/2J mice given 10(6) P-388 leukemia i.p. Mesna administered i.p. 5 min after cisplatin (6, 8 or 10 mg/kg) did not reduce cisplatins' antitumor efficacy in this same tumor model. Mesna appears to inactivate cisplatin directly in vitro but possibly not in vivo if separate injections are used.

Topics: Animals; Cisplatin; Drug Interactions; Leukemia P388; Male; Mercaptoethanol; Mesna; Mice; Mice, Nude