Cytotoxic Therapy . “Radiation Toxins”-possible new class of

Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.

Dmitri Popov MD (Russia), PhD (Russia-Canada)Advanced Medical Technology and Systems Inc.

intervaccine@gmail.comJeffrey Jones,

prof. at Baylor college of medicine.

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • Research Proposal:

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• Dmitri Popov• Full-text · Research Proposal · Feb 2016• Add resources• File name: Anticancer drugs class..pptx

DOI: 10.13140/RG.2.1.4243.8808

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • Isolation Radiation Toxins from irradiated plants and vaccination with

plant’s radiation toxins to radiation naïve mammals.• Isolation Radiation Toxins from irradiated mammals and vaccination

with “radiation toxins” to radiation naïve mammals.• “Radiation Toxins”-possible new class of Oncologic Drugs.:

Comparison of oncologic drugs by Mechanisms of Action.

Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • DNA-damaging agents have a long history of use in cancer chemotherapy. The full

extent of their cellular mechanisms, which is essential to balance efficacy and toxicity, is often unclear. In addition, the use of many anticancer drugs is limited by dose-limiting toxicities as well as the development of drug resistance. Novel anticancer compounds are continually being developed in the hopes of addressing these limitations; however, it is essential to be able to evaluate these compounds for their mechanisms of action.

• DNA-Damaging Agents in Cancer Chemotherapy: Serendipity and Chemical Biology. Kahlin Cheung-Ong,1 Guri Giaever,2 and Corey Nislow2, * 1Department of Molecular Genetics and the Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada 2Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada *Correspondence: corey.nislow@gmail.com http://dx.doi.org/10.1016/j.chembiol.2013.04.007

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • DNA integrity is critical for proper cellular function and proliferation.

High levels of damage to DNA are detected by cell-cycle checkpoint proteins, whose activation induces cell-cycle arrest to prevent the transmission of damaged DNA during mitosis.• http://dx.doi.org/10.1016/j.chembiol.2013.04.007

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • DNA lesions that occur during the S phase of the cell cycle block

replication fork progression and can lead to replication-associated DNA double-strand breaks (DSBs), which are among the most toxic of all DNA lesions. If the damaged DNA cannot be properly repaired, cell death may result.• http://dx.doi.org/10.1016/j.chembiol.2013.04.007

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • Cancer cells typically have relaxed DNA damage-sensing/repair

capabilities and, more importantly, they are capable of ignoring cell-cycle checkpoints, allowing the cells to achieve high proliferation rates; this also makes them more susceptible to DNA damage, since replicating damaged DNA increases the likelihood of cell death. • The concept of aiming at DNA as a target for anticancer drugs inspired

the development of numerous anticancer compounds, such as cisplatin, doxorubicin, 5-fluorouracil, etoposide, and gemcitabine.• http://dx.doi.org/10.1016/j.chembiol.2013.04.007

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • In the 1960s and 1970s, there was a surge of interest in developing

anticancer compounds that react chemically with DNA. • These included compounds that directly modify DNA bases,

intercalate between bases, or form crosslinks in DNA.• http://dx.doi.org/10.1016/j.chembiol.2013.04.007

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • DNA is under a constant stream of attack from various exogenous and

endogenous sources. Each mutagen can cause damage either directly or indirectly to the nucleotides in the genome. Moreover, each mutagenic agent shows a predilection for damaging specific nucleotides, which can produce recognizable patterns of mutagenesis.

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • Sources of DNA damage include endogenous factors such as

spontaneous or enzymatic conversions. The N-glycosidic bond that links a nucleobase and a pentose sugar to form a nucleoside is labile. This fact underlies the common occurrence of spontaneous base loss in DNA (~104bases per cell per day), which results in the formation of apurinic or apyrimidinic sites.• Mechanisms underlying mutational signatures in human cancers• Thomas Helleday et al. doi:10.1038/nrg3729

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • Other types of endogenous DNA damage include deamination,

replication errors and free radical species. Free radical species are generated either as a by-product of metabolism or through exposure to exogenous physical agents, such as ionizing radiation, which can induce the formation of double-strand breaks. By contrast, non-ionizing ultraviolet radiation is responsible for biochemical modifications, such as the formation of pyrimidine dimers, which can be mutagenic when left unrepaired.• Mechanisms underlying mutational signatures in human cancers• Thomas Helleday et al. doi:10.1038/nrg3729

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• Other external agents that are known to cause DNA damage include

chemical compounds, for example, platinum-based compounds such as cisplatin, which can cause bulky adducts or interstrand and intrastrand crosslinks; intercalating agents such as benzo[a]pyrenes, daunorubicin and actinomycin-D; DNA alkylating agents such as nitrogen mustards, methyl methanesulphonate (MMS), N-nitroso-N-methylurea (NMU) and N-ethyl-N-nitrosourea (ENU); and psoralens.• Mechanisms underlying mutational signatures in human cancers• Thomas Helleday et al. doi:10.1038/nrg3729

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• Dose-response curves were measured for the formation of direct-type

DNA products in X-irradiated d(GCACGCGTGC)(2)prepared as dry films and as crystalline powders. Damage to deoxyribose (dRib) was assessed by HPLC measurements of strand break products containing 3' or 5' terminal phosphate and free base release. Base damage was measured using GC/ MS after acid hydrolysis and trimethylsilylation.• http://www.ncbi.nlm.nih.gov/pubmed/17705640

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• http://www.ncbi.nlm.nih.gov/pubmed/19218779• After living cells are exposed to ionizing radiation, a variety of chemical

modifications of DNA are induced either directly by ionization of DNA or indirectly through interactions with water-derived radicals. The DNA lesions include single strand breaks (SSB), base lesions, sugar damage, and apurinic/apyrimidinic sites (AP sites).• The yield, processing, and biological consequences of clustered DNA

damage induced by ionizing radiation.• J Radiat Res. 2009 Jan;50(1):27-36• Shikazono N1, Noguchi M, Fujii K, Urushibara A, Yokoya A.

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• Clustered DNA damage, which is defined as two or more of such

lesions within one to two helical turns of DNA induced by a single radiation track, is considered to be a unique feature of ionizing radiation. A double strand break (DSB) is a type of clustered DNA damage, in which single strand breaks are formed on opposite strands in close proximity.• The yield, processing, and biological consequences of clustered DNA

damage induced by ionizing radiation.• J Radiat Res. 2009 Jan;50(1):27-36• Shikazono N1, Noguchi M, Fujii K, Urushibara A, Yokoya A.

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• The genomic integrity of every organism is constantly challenged by

endogenous and exogenous DNA-damaging factors. Mutagenic agents cause reduced stability of plant genome and have a deleterious effect on development, and in the case of crop species lead to yield reduction. It is crucial for all organisms, including plants, to develop efficient mechanisms for maintenance of the genome integrity.• http://www.ncbi.nlm.nih.gov/pubmed/26557130

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• DNA repair processes have been characterized in bacterial, fungal, and

mammalian model systems. The description of these processes in plants, in contrast, was initiated relatively recently and has been focused largely on the model plant Arabidopsis thaliana. Consequently, our knowledge about DNA repair in plant genomes - particularly in the genomes of crop plants - is by far more limited. However, the relatively small size of the Arabidopsis genome, its rapid life cycle and availability of various transformation methods make this species an attractive model for the study of eukaryotic DNA repair mechanisms and mutagenesis.• http://www.ncbi.nlm.nih.gov/pubmed/26557130

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• Abnormalities in DNA repair which proved to be lethal for animal

models are tolerated in plant genomes, although sensitivity to DNA damaging agents is retained. Due to the high conservation of DNA repair processes and factors mediating them among eukaryotes, genes and proteins that have been identified in model species may serve to identify homologous sequences in other species, including crop plants, in which these mechanisms are poorly understood.• http://www.ncbi.nlm.nih.gov/pubmed/26557130

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• http://

www.slideshare.net/dlpopov/radiation-toxicity-plants-toxicity-after-irradiation• http://

www.slideshare.net/dlpopov/radiation-toxins-effects-of-radiation-toxicity-molecular-mechanisms-of-action-radiomimetic-properties-and-possible-countermeasures-for-radiation-injury

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• Cytotoxic Therapy: Toxins. • http://www.slideshare.net/dlpopov/radiation-cytotoxicity• http://

www.slideshare.net/dlpopov/radiation-protectionprotease-inhibition

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• http://www.nature.com/cdd/journal/v18/n8/pdf/cdd201170a.pdf• Almost all plant cells have large vacuoles that contain both hydrolytic

enzymes and a variety of defense proteins. Plants use vacuoles and vacuolar contents for programmed cell death (PCD) in two different ways: for a destructive way and for a nondestructive way. Destruction is caused by vacuolar membrane collapse, followed by the release of vacuolar hydrolytic enzymes into the cytosol, resulting in rapid and direct cell death.

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• The destructive way is effective in the digestion of viruses proliferating

in the cytosol, in susceptible cell death induced by fungal toxins, and in developmental cell death to generate integuments (seed coats) and tracheary elements. On the other hand, the non-destructive way involves fusion of the vacuolar and the plasma membrane, which allows vacuolar defense proteins to be discharged into the extracellular space where the bacteria proliferate.• http://www.nature.com/cdd/journal/v18/n8/pdf/cdd201170a.pdf

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• Membrane fusion, which is normally suppressed, was triggered in a

proteasome-dependent manner. Intriguingly, both ways use enzymes with caspase-like activity; the membrane-fusion system uses proteasome subunit PBA1 with caspase-3-like activity, and the vacuolar-collapse system uses vacuolar processing enzyme (VPE) with caspase-1-like activity. This review summarizes two different ways of vacuole-mediated PCD and discusses how plants use them to attack pathogens that invade unexpectedly.• Cell Death and Differentiation (2011) 18, 1298–1304;

doi:10.1038/cdd.2011.70; published online 3 June 2011• I Hara-Nishimura*,1 and N Hatsugai2

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• Most vacuolar soluble proteins are synthesized on the endoplasmic

reticulum as larger precursors and then transported into vacuoles, where precursor proteins are converted into their respective mature forms by vacuolar processing enzyme (VPE). The machinery in plant cells is used to accumulate a variety of proteins in both types of vacuoles, hydrolytic enzymes including aspartate proteinases,9 cysteine proteinases, and nucleases required for non-selective degradation of cellular components during programmed cell death (PCD), and defense proteins including pathogenesis related proteins (PR proteins), myrosinases, toxic proteins, and lectin for defense against invading pathogens.• http://www.nature.com/cdd/journal/v18/n8/pdf/cdd201170a.pdf

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.• Hypersensitive cell death triggered by some pathogens is caused by

vacuole-mediated cell death, which is a type of plant-specific PCD. Using vacuoles for defense-related cell death makes sense for plants, because vacuoles exist in each cell of plants. • The question is, how are vacuoles used for cell death? There are two

different ways of vacuole-mediated cell death, a destructive type triggered by vacuolar membrane collapse and a non-destructive type involving no vacuolar membrane collapse.• http://www.nature.com/cdd/journal/v18/n8/pdf/cdd201170a.pdf

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • Oncologic drugs by mechanism of action:• 1. Damage DNA a. Alkylation b. Free Radical Formation • c. Inhibit synthesis and functions DNA. 1A. Antimetabolites.

1B. Topoisomerase inhibitors. • 4. Action on Mitotic Spindle. • 5. Action on Steroid hormone Receptors. • 6. Monoclonal Antibodies.• 7. Miscellaneous Actions.

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • DNA damage induces apoptosis of cells of hematological origin.

Apoptosis is also widely believed to be the major anti proliferative mechanism of DNA damaging anticancer drugs in other cell types.• Mechanisms of action of DNA-damaging anticancer drugs in

treatment of carcinomas: is acute apoptosis an "off-target" effect?• Havelka AM1, Berndtsson M, Olofsson MH, Shoshan MC, Linder S.• Mini Rev Med Chem. 2007 Oct;7(10):1035-9.

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • Recent studies have shown that cisplatin induces caspase activation in

enucleated cells (cytoplasts lacking a cell nucleus). Cisplatin-induced apoptosis in both cells and cytoplasts is associated with rapid induction of cellular reactive oxygen species and increases in [Ca(2+)].• Mechanisms of action of DNA-damaging anticancer drugs in

treatment of carcinomas: is acute apoptosis an "off-target" effect?• Havelka AM1, Berndtsson M, Olofsson MH, Shoshan MC, Linder S.• Mini Rev Med Chem. 2007 Oct;7(10):1035-9.•

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • Cisplatin has also been reported to induce clustering of Fas/CD95 in

the plasma membrane. Available data suggest that the primary responses to cisplatin-induced DNA damage are induction of long-term growth arrest ("premature cell senescence") and mitotic catastrophe, whereas acute apoptosis may be due to "off-target effects" not necessarily involving DNA damage.• Mechanisms of action of DNA-damaging anticancer drugs in

treatment of carcinomas: is acute apoptosis an "off-target" effect?• Havelka AM1, Berndtsson M, Olofsson MH, Shoshan MC, Linder S.• Mini Rev Med Chem. 2007 Oct;7(10):1035-9.

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action. • 1. Proteolytic enzymes exists in vacuoles of plant’s cells as a zymogen

non-active form. • 2. Radiation or other stress factors activate proteolytic enzymes.• 3. Proteolytic enzymes, isolated from irradiated plants, can be a active

and useful, effective component for cytotoxic therapy of human cancers.

“Radiation Toxins”-possible new class of Oncologic Drugs.: Comparison of oncologic drugs by Mechanisms of Action.