ABSTRACT
OBJECTIVE: Classical isobologram analysis offers a way for analysing combined drug effects in dose-response experiments statistically. The aim is to determine as to whether two agents or drugs can be considered synergistic or antagonistic in their effect. METHODS AND MATERIALS: We describe a MATLAB-based software tool for automated isobologram analysis and computation of combination indices. Statistical issues like estimation together with respective confidence intervals are of key interest. Additional predictive values are computed to facilitate a more easy interpretation of obtained results. RESULTS: Analysis of an experimental and a real in vitro data set demonstrates the approach and the way of interpreting results. Results are summarized in two ways: tables and graphical displays containing classical isobolograms. CONCLUSION: Our package supplements the clinical software-equipment and is a tool for automatic evaluation of combined dose-response experiments in experimental oncology in the urologic clinic.
Subject(s)
Antineoplastic Agents/pharmacology , Data Interpretation, Statistical , Dose-Response Relationship, Drug , Drug Interactions , Software , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Docetaxel , Fenretinide/pharmacology , Humans , Inhibitory Concentration 50 , Logistic Models , Male , Models, Statistical , Prostatic Neoplasms/drug therapy , Taxoids/pharmacologyABSTRACT
BACKGROUND: The platelet-derived growth factor receptor (PDFG-r), a tyrosine kinase, is expressed in 88% of primary prostate cancer and in 80% of the metastases. The tyrosine kinase inhibitor imatinib blocks the PDGF signaling pathway by inhibiting PDGF-r autophosphorylation. We examined the cytotoxic effects of imatinib in combination with other anticancer agents in the human prostate cancer cell lines LNCaP, PC-3, and DU 145. METHODS: The cells were exposed to imatinib and to the other drugs simultaneously for 5 days. Cell growth inhibition was determined by XTT assay. The cytotoxic effects in combinations were evaluated at the inhibitory concentration of 50% level by the isobologram. RESULTS: Imatinib produced additive effects with estramustine phosphate (EMP) and 4-hydroperoxy-cyclophosphamide in all three cell lines. In combination with etoposide imatinib produced additive effects in two of three cell lines. Imatinib with docetaxel produced antagonistic effects in PC-3 and additive to antagonistic effects in LNCaP and DU 145 cells. CONCLUSIONS: The simultaneous exposure of imatinib and EMP would be effective against hormone sensitive and hormone insensitive cell lines and this combination should be evaluated in clinical trials. In contrast, the simultaneous exposure of imatinib and docetaxel would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving imatinib in hormone-refractory prostate cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cyclophosphamide/analogs & derivatives , Piperazines/pharmacology , Prostatic Neoplasms/drug therapy , Pyrimidines/pharmacology , Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Benzamides , Cell Line, Tumor , Cyclophosphamide/pharmacology , Docetaxel , Drug Synergism , Estramustine/pharmacology , Etoposide/pharmacology , Humans , Imatinib Mesylate , Immunohistochemistry , In Vitro Techniques , Male , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-kit/metabolism , Receptors, Platelet-Derived Growth Factor/metabolism , Taxoids/pharmacologyABSTRACT
INTRODUCTION: Transfersomes (TF) are new, ultradeformable carriers with characteristics that enable them to penetrate the skin spontaneously. TFs are able to transport noninvasively both low- and high-molecular-weight molecules into the body. MATERIALS AND METHODS: TFs contain phosphatidylcholine and sodium cholate. Recombinant human interleukin-2 (Proleukin, Chiron) was added to the TFs and incubated for 24 h at 4 degrees C. The immunotransfersomes (ITF) were isolated from free interleukin-2 (IL-2) by filtration (Centrisart, Sartorius). Twenty-five thousand, 50,000 and 150,000 IU pure IL-2 and ITFs, which had been incubated with the same concentrations of IL-2, were applied subcutaneously (s.c.) (n = 8) and epicutaneously (e.c.) (n = 8) to mice. The IL-2 serum concentrations in the mice were then measured by ELISA after 2, 4, 6, 8, 10 and 24 h. Fractionation of the transdermal IL-2 application was also examined as a means of improving uptake. RESULTS: In concentrations of 25,000 and 50,000 IU IL-2, the subcutaneous application of ITFs resulted in a longer lasting IL-2 serum concentration than did the subcutaneous application of pure IL-2. While at 25,000 IU, the epicutaneous application of ITFs resulted in serum concentrations comparable to those resulting from s.c. application, at 50,000 and 150,000 IU, only 50% and 22.6% of the maximum serum concentration resulting from the s.c. application of pure IL-2 was obtained. Fractionating the transdermal IL-2 application improved uptake. CONCLUSION: We were able to show that biologically active IL-2 can be bonded to TFs up to 75%. It is possible to transport IL-2 through the skin using TFs. Both the concentration-dependent saturation of the TFs with IL-2 and fractionation of the application resulted in differing degrees of transcutaneous IL-2 uptake.
