Anti-cancer drug design
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Anti-cancer drug design · Jan 1997
Toxicological properties of several novel oligonucleotide analogs in mice.
The toxicological properties of ISIS 3082, a phosphorothioate oligonucleotide, and five structurally related analogs of ISIS 3082, were examined in Balb/c mice. Comparisons were made between the uniform phosphorothioate oligonucleotide (ISIS 3082), and a 2' propoxy modified phosphodiester (ISIS 9044), a 2' propoxy phosphorothioate (ISIS 9045), a chimeric oligonucleotide comprised of 2' propoxy diester wings and phosphorothioate deoxy center (ISIS 9046), a 5' C18 amine phosphorothioate (ISIS 9047), or a 5' cholesterol modified phosphorothioate (ISIS 8005) oligonucleotide. Oligonucleotides were administered at 50 mg/kg by i.v. bolus injection (tail vein) every other day for 14 days. ⋯ Kupffer cell hypertrophy and basophilic inclusions in Kupffer cells were observed in mice treated with ISIS 9045, ISIS 9047 and ISIS 8005, but not in ISIS 3082-treated mice. A unique renal lesions was noted in mice treated with ISIS 9044 only that was characterized as mild atrophy of proximal convoluted tubules associated with interstitial fibrosis. With the exception of the renal lesions observed in ISIS 9044 treated mice, the toxicity profiles of various oligonucleotide analogs examined in this study were similar to that observed for ISIS 3082.
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Anti-cancer drug design · Jul 1995
ReviewAntibody-directed enzyme prodrug therapy (ADEPT) with mustard prodrugs.
Antibody-directed enzyme prodrug therapy (ADEPT) is a two-step targeting procedure designed to improve the selectivity of anti-tumour agents. The approach is based on the activation of specially designed prodrugs by enzyme-antibody conjugates targeted to tumour-associated antigens. ⋯ The specific structural features required of the nitrogen mustard prodrugs, their design, syntheses, physicochemical properties, biological characteristics and activation to the corresponding drugs are reviewed. The ADEPT clinical trial with a nitrogen mustard prodrug is also discussed.
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Anti-cancer drug design · Oct 1994
Circumvention of platinum resistance: structure-activity relationship for homologous series of ammine/amine platinum(II) complexes in L1210 cell lines.
Ammine/amine dichloroplatinum(II) complexes have been evaluated for structure-activity relationship in wild-type L1210/0, 185-fold cisplatin-resistant L1210/DDP and 39-fold tetraplatin-resistant L1210/DACH murine leukemia cells. The mechanism of resistance in these cell lines is multifactorial, with DNA repair playing a dominant role. The amines incorporated in the complexes were selected from the alicyclic, heterocyclic and isoaliphatic class, and contained 3, 4, 5 or 6 carbon atoms. ⋯ Furthermore, the relationship between structure and resistance factor in L1210/DACH cells was in direct contrast to that seen in the L1210/DDP model in that the factors increased on ascending the homologous series stepwise. The lower members of the alicyclic and heterocyclic series and cisplatin had comparable resistance factors in the L1210/DACH line; higher members displayed resistance factors that were comparable to or greater than that of tetraplatin. These results provide evidence for amine class and size as factors that can modulate the potency and capacity of ammine/amine platinum complexes to circumvent cisplatin or tetraplatin resistance.
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Anti-cancer drug design · Nov 1991
Comparative StudyComparison of half-lives and cytotoxicity of N-chloroethyl-4-amino and N-mesyloxyethyl-benzoyl compounds, products of prodrugs in antibody-directed enzyme prodrug therapy (ADEPT).
The synthesis of two novel drugs, 4-[bis[2-(mesyloxy)ethyl]amino]benzoic acid (7) and 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]benzoic acid (8) is described here. They are the active drugs of two prodrugs (9 and 10) designed for use as anti-cancer agents. The prodrugs (9, 10 and 11) were made as a series of compounds which are bifunctional alkylating agents in which the activating effect of the ionized carboxyl function is masked through an amide bond to a glutamic acid residue. ⋯ The viability of two different tumour cell lines was monitored with each active drug and prodrug. The IC50 values varied from 65 to 625 microM for the active drugs: no IC50 values could be obtained for the prodrugs, using a rapid incubation procedure. Each in vitro technique demonstrated the ability of the glutamic acid moiety to deactivate the drugs, forming effective prodrugs.