Analysis of FDA Approved Anticancer Drugs Reveals the Future of Cancer Therapy

Blagosklonny, Mikhail V.

doi:10.4161/cc.3.8.1023

Cited by 128 publications

(60 citation statements)

References 64 publications

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“…This introduction of human constant domains led to the generation of the first chimeric mAb [33]. There are currently many chimeric antibodies in clinical utility such as rituximab, used in the treatment of CD20 positive B-cell non-Hodgkin's lymphoma [38]. Additional developments allowed for further decreases in immunogenicity by interchanging the murine hypervariable loops responsible for binding activity with their counter hypervariable loops in the human antibody.…”

Section: Protein-based Carrier Systemmentioning

confidence: 99%

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

et al. 2014

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Owing to their large size proteinaceous drugs offer higher operative information content compared to the small molecules that correspond to the traditional understanding of druglikeness. As a consequence these drugs allow developing patient-specific therapies that provide the means to go beyond the possibilities of current drug therapy. However, the efficacy of these strategies, in particular "personalized medicine", depends on precise information about individual target expression rates. Molecular imaging combines non-invasive imaging methods with tools of molecular and cellular biology and thus bridges current knowledge to the clinical use. Moreover, nuclear medicine techniques provide therapeutic applications with tracers that behave like the diagnostic tracer. The advantages of radioiodination, still the most versatile radiolabeling strategy, and other labeled compounds comprising covalently attached radioisotopes are compared to the use of chelator-protein conjugates that are complexed with metallic radioisotopes. With the techniques using radioactive isotopes as a reporting unit or even the therapeutic principle, care has to be taken to avoid cleavage of the radionuclide from the protein it is linked to. The tracers used in molecular imaging require labeling techniques that provide site specific conjugation and metabolic stability. Appropriate choice of the radionuclide allows tailoring the properties of the labeled protein to the application required. Until the event of positron emission tomography the spectrum of nuclides used to visualize cellular and biochemical processes was largely restricted to iodine isotopes and 99m-technetium. Today, several nuclides such as 18-fluorine, 68-gallium and 86-yttrium have fundamentally extended the possibilities of tracer design and in turn caused the need for the development of chemical methods for their conjugation.

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Section: Protein-based Carrier Systemmentioning

confidence: 99%

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

et al. 2014

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“…5,[37][38][39][40] Microtubule-targeting drugs kill proliferating cells. [6][7][8]41 Undesirably, mitotic inhibitors kill proliferating normal cells too.…”

Section: Protection Of Normal Cellsmentioning

confidence: 99%

The power of chemotherapeutic engineering: Arresting cell cycle and suppressing senescence to protect from mitotic inhibitors

Blagosklonny¹

2011

Cell Cycle

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“…These curative protocols could also include tissue-directed or cancer-specific therapy. 49,50 For example, a protocol can be started with relatively cancer-selective kinase inhibitors or tissue-directed therapies, both of which have high therapeutic windows but low efficacy. If cancer relapses, then restrictive combinations alternated with standard therapy could be applied in turn.…”

Section: Is Rc Curative?mentioning

confidence: 99%

“Targeting the absence” and therapeutic engineering for cancer therapy

Blagosklonny¹

2008

Cell Cycle

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IntroductionDiverse anti-cancer strategies are emerging. 1-25 These approaches are not mutually exclusive and will eventually complement each other. Alex Varshavsky has described how to design a molecular device, with potentially unlimited precision and selectivity. 1 It will recognize homozygous deletions (HDs) specific for cancer and restrict cytotoxicity to cancer cells.In contrast, the cytotoxicity of current small molecular drugs is not restricted to cancer cells. But what about drug combinations? In analogy, it is impossible to write Hamlet by using only one letter, but using a combination of letters, Shakespeare wrote Hamlet. Of course these combinations should not be scrambled. Currently, drugs are combined for synergy, to broaden the activity and to target all the variety of sub-clones in heterogenic cancer. Here we will discuss a completely different class of combinations: namely, restrictive combinations (RCs), designed to narrow the variety of targeted cells and to restrict cytotoxicity to those particular cells. Intriguingly, RCs and the Varshavsky device are based on similar principles. What are they? Varshavsky's DemonLet us consider, a DNA-vector 1 (or circuit or something that I will poetically call Demon for generalization and brevity). With a toxic payload (or a killer) and a sleeping guard in her pockets, Demon enters the cell, checking for DNA for the sequences that are absent in cancer cells. Once the sequences are found, the guard awakens and cuts Demon into peaces, disabling the payload. In cancer cells the DNA sequences are not found, the guard remains asleep and the toxic payload kills the cell.There are two points to emphasize. First, demon does not actually recognize cancer. It recognizes cellular context that in this case is highly specific for normal cells. Second, it employs a guard, who protects normal cells. In the Varshavsky scenario, both a guard and a killer are parts of the same vector. But generally speaking both activities could be independent. Demon Consisting of Two Small MoleculesThe first molecule checks cellular context. For example, it checks for the absence of functional wild type p53. How could that be done? To probe for p53 status, the first molecule (for example doxorubicin, DOX) damages DNA. DOX must be used at low doses (low-DOX) so it causes just a few random damages that are not lethal. 26,27 This is a test. In cells with p53, this test induces p53, which causes G1/G2 arrest. This arrest is the "guard" against the cytotoxicity of the second drug. Arriving independently, the second drug Taxol is a 'killer'. But Taxol kills cells only during mitosis. Then only cells with mutant p53 will be killed by Taxol. The cytotoxicity of low-Dox/Taxol is restricted to the cells with absent functional p53.The analogy with Varshavsky's Demon can be extended. There must be the lag time between the device entry and its cytotoxic action. 1 Otherwise normal cells will not be protected by a sleeping guard. After the lag time, a patient should receive an inducer that activates payl...

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Analysis of FDA Approved Anticancer Drugs Reveals the Future of Cancer Therapy

Cited by 128 publications

References 64 publications

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

The power of chemotherapeutic engineering: Arresting cell cycle and suppressing senescence to protect from mitotic inhibitors

“Targeting the absence” and therapeutic engineering for cancer therapy

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