Multidrug resistance (MDR) is a major impediment to the effective treatment of cancer. We have used multicellular tumor spheroids (MTS) as a model to investigate whether MDR can be reversed in a ...three dimensional structure. MTS are tightly associated aggregates of tumor cells that exhibit many of the properties of solid tumors. A human MDR breast carcinoma cell line was selected by exposure to taxol under monolayer conditions. The sensitive (parental) and drug-resistant phenotypes were retained when the cells were grown as MTS. Thus, the three dimensional conditions in this novel model system did not affect the MDR phenotype. SDZ PSC 833 is an efficient MDR reversing agent as determined under monolayer conditions and is currently being evaluated in clinical trials. Resistance to taxol and doxorubicin of the MDR cells grown as MTS was almost completely reversed by SDZ PSC 833. Our results suggest that SDZ PSC 833 has the potential to reverse the MDR phenotype in solid tumors.
Trifyl activation in organic synthesis Hendrickson, James B; Sternbach, Daniel D; Bair, Kenneth W
Accounts of chemical research,
08/1977, Letnik:
10, Številka:
8
Journal Article
Following recovery from a 4-hr exposure to clinically achievable concentrations of the topoisomerase II inhibitors Adriamycin, teniposide, or amsacrine or the putative topoisomerase II inhibitor ...crisnatol, murine erythroleukemic cells remained viable for up to 48 hr, but did not proliferate. Cell cycle analysis after a 24-hr recovery revealed blocks in G2 (4N DNA) or greater than G2 (up to 8N DNA) polyploid stages. The relative percentages of cells in either stage was a function of drug concentration and cell cycle stage at time of exposure: typically, cells exposed during S phase became blocked in G2, whereas those exposed during G2/M progressed into greater than G2 polyploid stages. G2-blocked cells exhibited a 2- to 3-fold increase in nuclear protein content and cellular/nuclear volume (i.e. unbalanced growth) and approximately 5% more DNA stainability (as a consequence of nuclear conformational changes rather than redundant DNA synthesis). In all cases, at the drug concentrations studied, mitotic figures were absent and G2 and greater than G2 blocks were irreversible, indicating that the mechanism of polyploidy induction differs from that of microtubule inhibitors. These findings suggest that although topoisomerase inhibitors interfere with DNA synthesis in the S phase, their induction of greater than G2 polyploid blocks may involve direct or indirect inhibition of chromosome condensation.
Synthesis of Isodehydroilludin M Kinder, Frederick R.; Chin, Jefferson; Shapiro, Michael J. ...
Synthetic communications,
19/7/1/, Letnik:
28, Številka:
13
Journal Article
Recenzirano
Isodehydroilludin M was synthesized from carbonyl ylid 1,3-dipolar cycloaddition product that was further elaborated with an unusual PCC-mediated double oxidation reaction.
A mechanism of action study was performed with 14 novel DNA binding agents characterized structurally as 2-(arylmethylamino)-1,3-propanediols (AMAPs). Correlations between 8226 myeloma cell colony ...formation and DNA damage were performed using soft agar colony-forming assays and alkaline elution filter techniques respectively. The frequency of double-stranded breaks (DSBs), single-stranded breaks (SSBs) and DNA-protein cross-links were compared with cell growth inhibitory potency. Highly potent AMAPs in the colony formation assays included 91U86, an N-methyl-5-benzo(c)carbazole derivative, 773U82, a 3-substituted fluoranthene derivative, and crisnatol (770U82), the 6-substituted chrysene derivative. There was a high frequency of SSBs and DSBs with many analogues, but only SSBs occurred in a concentration-dependent fashion. Using regression analysis, the degree of single-strand damage correlated with cytotoxic potency for the AMAPs, with an R-value of 0.57 (P = 0.04). By gel electrophoresis assays, three clinically tested AMAPs, crisnatol BW 770U82, BW 502U83 and BW 773U82, were shown to inhibit the decatenation of pBR 322 DNA by purified topoisomerase-II (TOPO-II) enzymes. These results suggest that while some active AMAPs, such as crisnatol (BW 770U82), BW 502U83 and BW 773U82, inhibit TOPO-II enzymes, leading to protein-associated SSBs, other mechanisms, which do not involve DNA strand damage, must also contribute to the cytotoxic effects of this class of antitumor compounds. Intercalation has been well documented for these drugs and this may explain some of the growth inhibitory activity of the AMAPs.
Conversion of triflones to ketones Hendrickson, James B; Bair, Kenneth W; Keehn, Philip M
Journal of organic chemistry,
08/1977, Letnik:
42, Številka:
17
Journal Article
The in vitro effects of the 2-(arylmethylamino)-1,3-propanediols (AMAPs) on macromolecular synthesis have been examined using the murine leukemia, P388, and the human mammary adenocarcinoma, MCF-7, ...under conditions of short-term drug exposure. AMAPs that were observed to inhibit macromolecular synthesis produced nearly equipotent inhibition of DNA and RNA synthesis. Equivalent inhibition of protein synthesis generally required significantly greater concentrations of AMAP. There is a general correlation between inhibition of polynucleotide synthesis and in vivo antitumor activity. The effects of four clinical candidate AMAPs (crisnatol, 773U82, 502U83, and 7U85) on macromolecular synthesis were further compared with those of actinomycin D, doxorubicin, mitoxantrone, etoposide, amsacrine, and cisplatin in MCF-7 cells. The pattern of AMAP action was most similar to that observed for doxorubicin and mitoxantrone. Finally, the effects of these four AMAPs on the size, specific activity, and rate of incorporation of 3H-dTTP into DNA of MCF-7 cells synchronized by pretreatment with hydroxyurea was determined. It was found that DNA synthesis was inhibited by AMAPs independent of inhibition of the uptake, phosphorylation, or retention of the metabolic precursors. These results support the theory that antitumor AMAPs interfere with the normal functioning of enzymes, such as topoisomerase II or DNA and RNA polymerases, which interact with DNA.
