Blockage of cyclin cdk's, PKC and phosphoinositol 3-kinase pathways leads to augmentation of apoptosis in drug-resistant leukemia cells: evidence for interactive effects of flavopiridol, LY 294002, roscovitine,wortmannin and UCN-01.

A mouse leukemia L1210 cell line (Y8), selected for resistance to deoxyadenosine, has a markedly altered phenotypic expression that includes loss of sensitivity to dATP as an allosteric inhibitor of ribonucleotide reductase, increased expression of c-myc, c-fos and WAF1/p21, but decreased expression of p53. In addition, the Y8 cells have a Very strong apoptotic response to a variety of agents under conditions in which the parental wild-type cells do not apoptose. In these studies, we show that flavopiridol (a cdk inhibitor) causes the Y8 cells to undergo apoptosis via a caspase-3 activation process.

Structure and dynamics of thioguanine-modified duplex DNA.

Mercaptopurine and thioguanine, two of the most widely used antileukemic agents, exert their cytotoxic, therapeutic effects by being incorporated into DNA as deoxy-6-thioguanosine. However, the molecular mechanism(s) by which incorporation of these thiopurines into DNA translates into cytotoxicity is unknown. The solution structure of thioguanine-modified duplex DNA presented here shows that the effects of the modification on DNA structure were subtle and localized to the modified base pair.

In vivo growth of mouse leukemia L1210 cells with metabolic alterations in the subunits of ribonucleotide reductase.

Mouse leukemia L1210 cells selected for resistance to drugs targeted specifically at each of the protein subunits of ribonucleotide reductase were studied for their ability to grow in vivo. The life-span of the mice injected with hydroxyurea-resistant L1210 cells, which have elevated levels of the mRNA and protein for the non-heme iron (NHI, R2) subunit of ribonucleotide reductase, was approximately twice that of the mice injected with equal numbers of the parental wild-type L1210 leukemia cells. The life-span of mice injected with the L1210 cells that had alterations in the effector-binding subunit (EB, R1) was considerably shorter than the mice injected with the parental wild-type L1210 cells.