Novel RHD alleles with weak hemagglutination and genetic Exon 9 diversity: weak D Types 45.1, 75, and 76.

Background: Molecular variant RHD allele analysis is best complemented by detailed characterization of the associated D phenotype.

Study Design And Methods: Variant D types were characterized using molecular typing, RHD sequencing, extended serologic D antigen investigations, and flow cytometric D antigen quantification.

Results: We discovered three novel weak D types termed weak D Types 45.

Fyx is associated with two missense point mutations in its gene and can be detected by PCR-SSP.

The Duffy blood group antigens are encoded by the Duffy gene with its three major alleles: Fy*A (Fya+), Fy*B (Fyb+), and a nonexpressed Fy*Fy (Fya-b-), which is most commonly found among black people. Additionally, a fourth allele, Fyx, is found among white people and defined as weak Fyb not detectable by all anti-Fyb. Three polymerase chain reactions (PCRs) using sequence-specific priming (SSP) for detection of the major FY alleles were developed.

PKC-independent modulation of multidrug resistance in cells with mutant (V185) but not wild-type (G185) P-glycoprotein by bryostatin 1.

Bryostatin 1 is a new antitumor agent which modulates the enzyme activity of protein kinase C (PKC, phospholipid-Ca2+-dependent ATP:protein transferase, EC 2.7.1.

Reversal of multidrug resistance by the staurosporine derivatives CGP 41251 and CGP 42700.

It has been shown previously that the staurosporine derivative CGP 41251, a specific inhibitor of protein kinase C (IC50 = 50 nM), exhibits antitumor activity and reverses mdr1 mediated multidrug resistance. At present, the compound is evaluated as an anticancer drug in clinical phase I trials. We compared the effects of CGP 41251 with CGP 42700, another staurosporine derivative, which exhibits low protein kinase C inhibiting activity (IC50 = > 100 microM).

Resistance to the new anti-cancer phospholipid ilmofosine (BM 41 440).

The thioether phospholipid ilmofosine (BM 41 440) is a new anti-cancer drug presently undergoing phase II clinical trials. Because resistance to anti-tumour drugs is a major problem in cancer treatment, we investigated the resistance of different cell lines to this compound. Here we report that the multidrug-resistant cell lines MCF7/ADR, CCRFNCR1000, CCRF/ADR500, CEM/VLB100 and HeLa cell lines transfected with a wild-type and mutated (gly/val185) multidrug resistance 1 gene (MDR1) are cross-resistant to ilmofosine compared with the sensitive parental cell lines.

Effects of the selective bisindolylmaleimide protein kinase C inhibitor GF 109203X on P-glycoprotein-mediated multidrug resistance.

Inhibition of protein kinase C (PKC) is discussed as a new approach for overcoming multidrug resistance (MDR) in cancer chemotherapy. For evaluation of this concept we applied the bisindolylmaleimide GF 109203X, which shows a highly selective inhibition of PKC isozymes alpha, beta 1, beta 2, gamma, delta and epsilon in vitro. The efficacy of this compound in modulation of MDR was examined using several P-glycoprotein (P-gp)-overexpressing cell lines including a MDR1-transfected HeLa clone, and was compared with the activities of dexniguldipine-HCI (DNIG) and dexverapamil-HC1 (DVER), both of which essentially act via binding to P-gp.

Protein kinase C isoenzymes, p53, accumulation of rhodamine 123, glutathione-S-transferase, topoisomerase II and MRP in multidrug resistant cell lines.

We investigated whether the expression of protein kinase C (PKC) isoenzymes, topoisomerase II alpha, II beta, multidrug resistance associated protein (MRP), p53 or the activity of glutathione-S- transferase (GST) are additional factors contributing to the resistance mediated by multidrug resistance gene 1 (mdr 1). the cell lines employed for these studies were human lymphoblastoid CCRF cells selected for resistance with actinomycin D, vincristine and adriamycin, KB-3-1 and matched resistant KB-8-5 and KB-C1 cells (selected with colchicine), and a HeLa cell line, in which the resistance was obtained by transfection with the mdr1-gene. Analysis of PKC isozymes showed that there is no correlation of a specific isoenzyme with resistance, although minor differences in the expression were observed.

Mechanism of action of dexniguldipine-HCl (B8509-035), a new potent modulator of multidrug resistance.

It has previously been shown that dexniguldipine-HCl (B8509-035) is a potent chemosensitizer in multidrug resistant cells [Hofmann et al., J Cancer Res Clin Oncol 118: 361-366, 1992]. It is shown here that dexniguldipine-HCl causes a dose-dependent reduction of the labeling of the P-glycoprotein by azidopine, indicating a competition of dexniguldipine-HCl with the photoaffinity label for the multidrug resistance gene 1 (MDR-1) product.

The protein kinase C inhibitor CGP 41251, a staurosporine derivative with antitumor activity, reverses multidrug resistance.

Multidrug resistance (MDR) is frequently associated with overexpression of a 170-kDa P-glycoprotein (Pgp). Data suggest altered protein kinase C (PKC) activity in cells expressing the multidrug-resistant phenotype. The staurosporine derivative CGP 41251, an experimental anticancer drug, has been shown to exert selectivity for inhibition of protein kinase C activity and to exhibit antitumor activity in vitro and in vivo.

Role of protein kinases in antitumor drug resistance.

The activity of several proteins involved in the development of antitumor drug resistance is regulated by protein phosphorylation. These proteins include the mdr-1-encoded P-glycoprotein (Pgp) and topoisomerase II (topo II). The corresponding evidence is reviewed and attempts to modulate multidrug resistance (MDR) by protein kinase C inhibitors are described.