Cytotoxic Therapy. “Radiation Toxins”-possible new class of Anti Cancer Drugs.: Comparison of anticancer drugs by Mechanisms of Action.

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.com
Jeffrey 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

• 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
• 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

• 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

• 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.

• 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.

• 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.

• 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.

• 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

• 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.

• 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.

• 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

• 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.

• 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.

• 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.

• 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.

• 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.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

• Cytotoxic Therapy: Toxins.
• http://www.slideshare.net/dlpopov/radiation-cytotoxicity
• http://www.slideshare.net/dlpopov/radiation-protectionprotease-
inhibition

• 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.

• 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.

• 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

• 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.

• 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.

• 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.

• 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.

• 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+)].
•

• 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.

• 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.

Cytotoxic Therapy. “Radiation Toxins”-possible new class of Anti Cancer Drugs.: Comparison of anticancer drugs by Mechanisms of Action.

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Cytotoxic Therapy. “Radiation Toxins”-possible new class of Anti Cancer Drugs.: Comparison of anticancer drugs by Mechanisms of Action.