MMDX metabolites are very potent but display a lower degree of tumor selectivity than MMDX. Strategies to reduce MMDX metabolization should be developed to optimize the therapeutic index of this new anthracycline.
Anticancer agents targeting proliferating cell populations in tumor as well as in normal tissues can lead to a number of side effects including hematotoxicity, a common dose-limiting toxicity associated with oncology drugs. Myelosuppression, regarded as unacceptable for other therapeutic indications, is considered a clinical risk also for new targeted anticancer drugs acting specifically on tumor cells. Thus, it becomes important not only to evaluate the potential toxicity of such new therapeutics to human hematopoietic tissue during preclinical development but also to anticipate this liability in early drug discovery. This could be achieved by using in silico models to guide the design of new lead compounds and the selection of analogs with reduced myelosuppressive potential. Hence, the purpose of this study was to develop computational models able to predict the potential myelotoxicity of drugs from their chemical structure. The data set analyzed included 38 drugs. The structural diversity and the drug-like space covered by these molecules were investigated using the ChemGPS methodology. Two sets of potentially relevant descriptors for modeling myelotoxicity (i.e., 3D Volsurf+ and 2D structural and electrotopological E-states descriptors) were selected and a Principal Component Analysis was carried out on the entire set of data. The first two PCs were able to discriminate the highest from the least myelotoxic compounds with a total accuracy of 95%. Then, a quantitative PLS model was developed by correlating a selected subset of in vitro hematotoxicity data with Volsurf+ descriptors. After variable selection, the PLS analysis resulted in a one-latent-variable model with r(2) of 0.79 and q(2) of 0.72. The inclusion of 2D descriptors in the PLS analysis improved only slightly the robustness and quality of the model that predicted the pIC(50) values of 21 drugs not included in the model with a RMSEP of 0.67 and a squared correlation coefficient (r(0)(2)) of 0.70. Furthermore, in order to investigate whether the highly myelotoxic compounds are characterized by common structural features, which should be taken into consideration in the design of new candidate drugs, the entire data set was analyzed using GRIND toxicophore-based descriptors. One toxicophore emerged from the interpretation of the model. The toxicophore elements, at least determined by the molecules used in this study, are a pattern of H-bond acceptor groups, presence of a H-bond donor and H-bond acceptor regions at ∼15 Å distance and a hydrophobic and H-bond acceptor interacting regions separated by a distance of ∼12.4 Å. Moreover, the dimensions of the molecule play a role in its recognition as a myelotoxic compound.
We investigated the mechanism of resistance in murine L1210 leukaemia cells selected after treatment with FCE 23762 methoxymorpholinyl doxorubicin: (MMRDX), a methoxymorpholinyl derivative of doxorubicin active in vitro and in vivo on multidrug-resistant (mdr) cells, currently undergoing phase I clinical trials. The resistant subline obtained after repeated in vitro treatments, L1210/MMRDX, is resistant in vitro and in vivo to all tested methoxymorpholinyl derivatives and to cyanomorpholinyl doxorubicin, but shows resistance to morpholinyl derivatives only in vivo or following their activation with rat S9-liver fractions in vitro. L1210/MMRDX cells are sensitive to classic mdr- and altered topoisomerase (AT)-mdr-associated drugs. These cells do not appear to overexpress the mdr1 gene, nor do they exhibit impaired intracellular drug accumulation and efflux or altered levels of glutathione and glutathione S-transferase. The extent of DNA single-strand break formation and, after microsomal activation, of DNA interstrand cross-links after treatment with MMRDX was similar in the parent and the resistant subline. The mechanism of resistance in L1210/MMRDX cells remains to be identified but may prove a novel one, highly specific for this class of mdr-active anthracyclines.
Summary Resistance to FCE 24517 is not related to the emergence of any of the most frequently observed phenotypes. We have found that two resistant cell lines (L1210/24517 murine leukaemia and LoVo/24517 human colon adenocarcinoma) present congenital modifications in tyrosyl phosphatase and kinase activities. Moreover, the cytotoxic activity of FCE 24517 is increased in combination with a tyrosine phosphatase inhibitor and decreased in combination with protein kinase inhibitors, this being in agreement with the hypothesis that the activity of this drug is strictly dependent on the presence of tyrosine phosphorylated protein(s).
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