Adriamycin cellular effects

The use of triphenylethylene SERMs as Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration, which is likely due to the involvement of proteins with the ability to bind these compounds. For instance, toremifene is able to reverse MDR and to sensitize human renal cancer cells to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular a 1-acid glycoprotein (AAG), which may limit its tissue availability (Braybrooke et al. 2000). In agreement with this, Chatterjee and Harris (1990) have shown that tamoxifen and 4-OH-tamoxifen were similarly potent in reversing MDR in Chinese hamster ovary (CHO) cells with acquired resistance to adriamycin. However, the addition of AAG (0.5 to 2 mg/ml, the range found in vivo) to cell cultures decreased the effect of tamoxifen on reversing MDR, and at the highest AAG concentration there was a complete reversal of the effects of... 

Guffy, M. M., North, J. A., and Bums, C. P., 1984, Effect of cellular fatty acid alteration on adriamycin sensitivity in cultured L1210 murine leukemia cells, Cancer Res. 44 1863-1866. 

Short term treatment with TPA sensitized human 2008 ovarian carcinoma cells to cis-platin. This sensitization disappeared completely by seven hours after treatment, indicating that not inhibition, but activation of PKC sensitizes 2008 cells to the antiproliferative activity of cis-platin (Isonishi et al., 1990). Pretreatment of HeLa cells with TPA or PdBu caused a 9-fold increase in cellular sensitivity to cis-platin and 2.5-fold to melphalan, but had now effect on the antiproliferative activity of bleomycin, adriamycin, vincristine, or mitomycin C. The sensitization of HeLa cells by TPA was associated with a 6-fold stimulation of PKC activation and a concentration- and time-dependent increase in cellular platinum content. (Basu et al. 1990). PKC activity was found to be decreased significantly in cis-platin-resistant human small cell lung H69/CP cancer cells compared to the drug-sensitive variant. A similar reduction in PKC activity was noted in ovarian carcinoma 2008 cells that were resistant to cis-platin. A modest decrease in PKC activity was also observed in etoposide-resistant H69 cells but not in taxol-resistant H69 cells or bleomycin-resistant human head and neck carcinoma A-253 cells (Basu et al., 1996), indicating that reduced PKC activity leads to decreased sensitivity in this system. 

Tsuruo T, Iida H, Kitatani Y, et al. Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and adriamycin in drug-resistant tumor cells. Cancer Res 1984 44(10) 4303 4307. 

Adriamycin is completely without effect on cell proliferation in severely iron-deficient Euglena gracilis and has substantially diminished activity in the Fe-deficient mammalian HL-60 tumor and H9c2 (2-1) heart myoblast cell lines. ° Thus, the availability of cellular iron is necessary for much, if not all, of the cytotoxic effects of Adr in tumor and cardiac cell models. 

All the effects on cellular processes, discussed above, are consistent with intercalation into cellular DNA as the molecular mode of action of adriamycin and daunomycin. The broad structural requirements for action at the cellular level have been outlined above, and it is likely that the model of the DNA complex will be reflned as more information becomes available. This detailed knowledge of the interaction with DNA presents a rare opportunity for the rational... 

The pharmacokinetics, pharmacology, chemotherapeutic effects, toxicity, chromosome aberatlons and mutagenic potency of adriamycin were reported. 105-109 Adriamycin is useful for acute lymphoblastic and chronic myelogenous leukemias, transitional cell carcinoma, llposarcoma, squamous cell carcinoma, and adenocarcinoma of the breast. It is less toxic than daunorubicin. Resistance to daunorubicin is due to changes in the cellular membrane.no Both antibiotics possess Immunosuppressive properties.HI... 

---