Anticancer Therapies Radiation and Drugs Flashcards
Key properties of cancer cell (2)
They reproduce without regard to the normal restraints on cell growth and cell division
They invade and colonize areas normally reserved for other cells
Tumors or neoplasms are abnormal cells that (2)
grow (increases in mass) and proliferate (divides)
Tumors are considered — if the neoplastic cells do not become invasive
benign
Tumors are considered cancerous if it acquires the ability to invade surrounding tissue at which point it is has become —
malignant
Malignant tumors often, as a consequence of
their invasiveness, produce cells that break
out of their primary site and form secondary
tumors at other sites called —
metastases
is a single mutation sufficient to cause cancer?
no
inherited mutations confer increased…
risk of developing cancer
potential risk factors (5)
radiation exposure UV light from the sun chemicals (carcinogens) life style (smoking, certain diets) viruses (EBV, HIV, HPV)
overall incidence of cancer increases with
age
During the cell-cycle the cell has scanning
mechanisms to detect DNA damage and either
(2)
repair the damage or result in cell-cycle arrest
or cell death (apoptosis)
A key mechanism in the cellular response to
DNA damage is mediated by the protein, —
p53
Improved cancer survival rates has been achieved through
combination therapies that are the standard of care today
In addition to the battery of drugs, (2) remain an effective (co-)treatment for many forms of cancer
surgical removal of the tumor and radiation therapy
The basic strategy for treating cancer with
either drugs or radiation is to
induce so much
damage to the tumor cells via DNA damage
(primarily) to prevent them from dividing and
induce cell death
The unfortunate side-effects result from the
same damage potentially occurring in
normal cells
External Beam Therapy
Uses a machine to send high energy beams from outside the body to the tumor area
Internal Radiation Therapy
Radioisotope given internally, radiation generally only travels a short distance depending upon the isotope and its energy
Radiation induces — —, which leads
to — —
DNA damage
cell death
Photon therapy (X-ray/Gamma rays): works either by (2)
direct ionization of atoms in the DNA chain or indirectly by ionization of water to form hydroxyl radicals that can then damage DNA
— — generate energies of 20-150 kV, while most X-ray energies in radiation therapy run in the range of 1-25 MV
Diagnostic X-rays
Other photon beams derived from iridium-192, cesium-137 or cobalt-60 generate — rays with an energy range of 300 keV -1.5MeV
gamma
Charged Particle or Proton therapy
uses a particle accelerator to beam high-energy particles (protons or carbon, boron or neon nuclei)
advantage of charged particle or proton therapy
Better ability to precisely localize the radiation dosage and less damage to surrounding, healthy tissue
Doxorubicin hydrochloride (adriamycin) (2)
Doxorubicin intercalates between base pairs in the DNA helix, thereby preventing DNA replication and ultimately inhibiting protein synthesis
Doxorubicin also forms oxygen free radicals resulting in cytotoxicity secondary to lipid peroxidation of cell membrane lipids
Bleomycin sulfate (1)
forms complexes with iron that
reduce molecular oxygen to superoxide and hydroxyl radicals
which cause single- and double-stranded breaks in DNA
Cisplatin (1)
forms highly reactive, charged, platinum
complexes which bind to nucleophilic groups such as GC-
rich sites in DNA, inducing intrastrand and interstrand
DNA cross-links, as well as DNA-protein cross-links
Methotrexate (1)
inhibits the enzyme
dihydrofolate reductase, resulting in inhibition of purine
nucleotide and thymidylate synthesis
Vinblastine (1)
Vinblastine binds to tubulin and inhibits
microtubule formation, resulting in disruption of mitotic
spindle assembly and arrest of tumor cells in the M
phase of the cell cycle.
Vincristine (1)
Vincristine binds irreversibly to microtubules and spindle
proteins in S phase of the cell cycle and interferes with the
formation of the mitotic spindle, thereby arresting tumor cells
in metaphase.
Prednisolone (2)
binds to and activates specific nuclear receptors,
resulting in an altered gene expression and inhibition of
proinflammatory cytokine production
stimulates apoptosis in sensitive tumor
cells populations.
Immunotherapy is a treatment designed to (3)
induce, enhance or suppress the immune response
Most applications are designed to stimulate a
person’s own immune response to destroy cancer cells that have escaped normal immune surveillance
Opdivo and Keytruda target
PD-1 on T-cells (also highly expressed on some type of tumors)
Opdivo and Keytruda target PD-1 on T-cells (also highly expressed on some type of tumors). It has been shown to help shrink or slow growth of tumors such as (3)
melanoma, non-small cell lung cancer, Hodgkin lymphoma, others
Opdivo and Keytruda target PD-1 on T-cells (also highly expressed on some type of tumors). It has been shown to help shrink or slow growth of tumors such as (3)
melanoma, non-small cell lung cancer, Hodgkin lymphoma, others
PD-1 is part of an immune checkpoint control system that keeps immune cells from
attacking “self”
CML
Chronic Myelogenous Leukemia
Leukemia characterized by
increased
production/growth of myeloid cells in the bone
marrow that then circulate in the blood
what is CML. caused by
a chromosomal translocation called the Philadelphia chromosome
the translocation creases a
fusion gene/protein between the BCR and ABL gene
fusion protein is a
tyrosine kinase
long term survival rates of CML
> 95%
what is the parent drug used to treat CML?
Gleevec (imatinib)
treatment phases for leukemia (3)
induction therapy
consolidation/intensification therapy
maintenance therapy
Induction therapy
this is the first phase of treatment. The goal is to kill the leukemia cells in the blood and bone marrow. This puts the leukemia into remission. This is also called the remission induction phase.
Consolidation/intensification therapy
This is the second phase of therapy. It begins once the leukemia is in remission. The goal of consolidation/intensification therapy is to kill any remaining leukemia cells that may not be active but could begin to regrow and cause a relapse
Maintenance therapy
This is the third phase of treatment. The goal is to kill any remaining leukemia cells that may regrow and cause a relapse. Often the cancer treatments are given in lower doses than those used for induction and consolidation/intensification therapy. This is also called the continuation therapy phase.
AML
acute myeloid leukemia
how many subtypes of AML?
8 (M0-M7)
what are the 8 subtypes of AML based upon?
the cell that the leukemia develops from and many have chromosomal translocations that create fusion proteins
AML M3
acute promyelocytic leukemia
patients with AML M3 can develop
blood clotting and bleeding problems
AML M3: — — of the retinoic acid receptor-alpha gene (RARA) on Cs17 with the PML gene on Cs15. Other translocations have also been described with RARA.
Chromosomal tranlocation
treatment of AML M3 (3)
– Induction: all-trans-retinoic acid (ATRA, tretinoin), often combined with daunorubicin or idarubicin, sometimes with ara-C
– Consolidation: anthracycline with ATRA (few cycles), anthracycline plus ara-C (2 cycles), arsenic trioxide (2 cycles then ATRA + anthracycline for 2 cyles, ATRA + arsenic trioxide for several cycles.
– Maintenance: mainly ATRA for at least a year.
Fusion protein has — function
altered
It binds with high affinity to sites on the DNA important for — differentiation.
granulocyte
the blocking of differentiation involves enhanced interactions of (2)
the nuclear co-repressor (NCOR) and histone deacetylase (HDAC)
ATRA does not kill the immature leukemic promyelocytes, but induces
their terminal differentiation and then these differentiated malignant cells undergo apoptosis
ATRA induces the dissociation of NCOR and HDAC allowing for
differentiation to proceed
ALL
acute lymphoblastic leukemia
ALL
bone marrow produces too many immature lymphocytes (at the expense of other blood cell types)
ALL risk factors (5)
• Being exposed to x-rays before birth.
• Being exposed to radiation.
• Past treatment with chemotherapy.
• Having certain changes in the genes.
• Having certain genetic conditions that include the following:
– Down syndrome, Ataxia telangiectasia, Bloom syndrome, Neurofibramatosis, Schwachman Syndrome.
possible signs and symptoms of ALL
Fever; foul smelling urine; easy bruising or bleeding; petechiae (flat, pinpoint, dark-red spots under the skin caused by bleeding); bone or joint pain; painless lumps in the neck, underarm, stomach or groin; pain or feeling of fullness below the ribs; weakness, feeling tired, or looking pale; loss of appetite.
diagnosis of ALL
Blood CBC (complete blood count), bone marrow analysis, cytogenetic analysis
ALL prognosis can depend upon… (7)
- Age at diagnosis, gender, and race.
- The number of white blood cells at diagnosis.
- Whether the leukemia cells began from B lymphocytes or T lymphocytes.
- Whether there are certain changes in the chromosomes of lymphocytes.
- Whether the child has Down syndrome.
- Whether the leukemia has spread to the brain, spinal cord or testicle.
- How quickly and how low the leukemia cell count drops after initial treatment.
ALL risk groups (2)
standard (low) risk
high risk
Standard (low) risk
Includes children aged 1
to younger than 10 years who have a WBC
count of less than 50,000/μL at diagnosis.
High risk
Includes children younger than 1
year or 10 years and older and children who
have a white blood cell count of 50,000/μL or
more at diagnosis.
The National Cancer Institute has identified
— plants that are active against cancer
cells. –% of these plants are found in the
rainforest.
3000
70%
–% of the active ingredients in today’s cancer
25%
-fighting drugs come from organisms found
only in the rainforest
Our understanding of the genetics of cancer
has — exponentially in the last 20
years
increased
New drugs continue to be developed,
but the reality is we
still have a long way to go
in our quest to cure cancer
Tissues not made up only of
cells
Extracellular space is filled with network of large
macromolecules (ECM)
ECM is composed from
large repertoire of specialized ECM proteins with various properties assembled into an organized
network/meshwork, often in close association with producer cells
connective tissues
specialized tissues in which ECM is more abundant than cells
ECM is critical in many oral and cranioacial tissues such as (4)
teeth/bone
cartilage
lamina propria beneath oral epithelium
gingiva, periodontium
teeth/bone
specialized mineralized connective tissues
cartilage
proteoglycan-rich specialized connective
tissue
Lamina Propria beneath oral epithelium
composed of collagen fibers in a connective tissue or STROMAL matrix (similar to dermis of skin)
Gingiva, periodontium
have a stromal matrix
containing collagen
stroma
cell embedded in matrix
Major components of STROMAL MATRIX
collagen embedded in polysaccharide ground
substance of hyaluronan +
proteoglycans/glyosaminoglycans
stromal cells are derived from the
mesodermal lineage
fibroblasts secrete — in most connective tissue
ECM
in specialized tissues, ECM is secreted by other fibroblast-related cells, such as (3)
osetoblasts
chondrocytes
odontoblasts
basal lamina
Specialized matrix at interface between
connective tissue stroma and epithelium
(separates them/anchors them)
Basal lamina is tethered to underlying
connective tissue by
type VII collagen
anchoring fibrils (“Basement membrane” –
refers to the basal lamina combined with
this layer of collagen fibrils)
basal lamina is important in cell —
polarity
major protein of the tissue
ECM
ECM is traditionally viewed as structurally stable material whose function is to provide
support/anchorage to cells and tissues/demarcate boundaries between cells/tissues
function of ECM in bone (3)
- Support and locomotion
- Calcium homeostasis
- Skeleton protects brain, internal organs
function of ECM in teeth (2)
- Provides strength/structure to tooth
- Resists shear and compression forces associated with chewing
function of ECM in teeth (2)
- Provides strength/structure to tooth
- Resists shear and compression forces associated with chewing
function of ECM in cartilage (2)
- support and locomotion
- resilient -shock absorber for compressive forces associated with locomotion, mastication, etc
ECM roles in addition to structural roles (4)
- Embryonic Development (cell adhesion / migration / tissue morphogenesis)
- Regulation of Cell Function (signaling / growth / differentiation)
- Tissue Repair/wound healing
- Angiogenesis
Composition of ECM in each tissue is perfectly suited to — requirements of the tissue
biomechanical/functional
ECM can be viewed as composite material, as in
various building materials (macromolecules) with different mechanical properties combined/organized to create a tissue with
optimal mechanical properties
Genes encode for large repertoire of ECM components, which can be used to
assemble ideal extracellular matrix for given tissue
examples of diverse types of ECM (3)
bone/teeth: calcified, hard ECM
cornea: optically transparent ECM
tendon: rope-like organization of collagen gives tensile strength in one direction
property of collagen (fibrillar)
tensile strength
property of proteoglycans
resilience/resistance to compression
property of elastin (elastic fibers)
elasticity/resilience
property of fibrin-1 (microfibrils)
controlled elasticity
property of mineral (hydroxyapatite)
strength, hardness, but also brittleness
