PubMed · 8850708
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V Fouquoire. 1996. [Antineoplastic agents. Part 1].. https://pubmed.ncbi.nlm.nih.gov/8850708/
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Drug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.
The requirement for novel platinum antitumor drugs led to the synthesis of dinuclear bisplatinum complexes. To understand the molecular mechanisms underlying the biological activity of this new class of platinum cytostatics, modifications of natural DNA and synthetic oligodeoxyribonucleotide duplexes by dinuclear bisplatinum complexes with equivalent monofunctional coordination spheres, represented by the general formula [{cis-PtCl(NH(3))(2)}(2)(H(2)N-R-NH(2)](2+) (1,1/c,c), in which R is a linear alkane chain, butane or hexane, were studied by various biochemical and molecular biology methods. The results indicated that the major adducts of 1,1/c,c complexes in DNA ( approximately 90%) were interstrand cross-links preferentially formed between guanine residues. Besides 1,2 interstrand cross-links (between guanine residues in neighboring base pairs), 1,3 or 1,4 interstrand cross-links were also possible. In the latter two long-range adducts, the sites involved in the cross-links were separated by one or two base pairs. 1,2, 1,3, and 1,4 interstrand cross-links were formed with a similar rate and were preferentially oriented in the 5' --> 5' direction. In addition, the DNA adducts of these complexes inhibited DNA transcription in vitro. Thus, the binding of the 1,1/c, c complexes modifies DNA in a way that is distinctly different from the modification by the antitumor drug cisplatin. In addition, there are significant differences between the dinuclear 1,1/c,c and 1,1/t, t isomers. The results of this work are consistent with the hypothesis and support the view that platinum drugs that bind to DNA in a fundamentally different manner can exhibit different biological properties including the spectrum and intensity of antitumor activity. The intracellular DNA binding of the dinuclear compounds is compared to the results presented here. It has been suggested that differences in cross-link structure may be an important factor underlying their different biological efficiencies.
Damage to DNA has been implicated in the induction of permanent cell cycle arrest or premature senescence in normal human fibroblasts. We tested the ability of a group of cancer chemotherapeutic agents or related compounds, which can cause DNA double-strand breaks (DSBs) directly or indirectly, to induce a permanent cell cycle arrest in normal proliferating fibroblasts. A brief treatment with etoposide, doxorubicin, cisplatin, or phleomycin D1 induced a block to S phase entry sustained through 15 days. Lower levels of these drugs did not induce appreciable levels of transient cell cycle arrest. Higher concentrations caused cell death that lacked the DNA degradation characteristic of apoptosis. Camptothecin, an agent that causes DNA single-strand breaks, which are converted to DSBs during S phase, was able to induce an efficient, but only transient, cell cycle arrest in these normal cells. The cells did not enter S phase until after removal of the camptothecin. These findings support the idea that permanent cell cycle arrest and cell death are typical reactions of these normal cells to drugs that can cause DSBs. In addition, we report data consistent with the concept that both actinomycin D and doxorubicin are sequestered by cells and slowly released in active form. This is consistent with the observation that both these drugs bind reversibly to intracellular components.