Cancer 1 Flashcards
1
Q
Cancer Biology
A
- cancer is a group of more than 100 diseases
- second leading cause of death
- more than 1 million new cases each year
2
Q
Pancreatic Cancer Stats
A
- estimated new cases 45,220
- estimated deaths 38,460
- the number of new cases and estimated deaths are both still going up
3
Q
Molecular Basis of Cancer
A
- cancer is a genetic disease, but other epigenetic changes also occur
- it is characterized by abnormal cellular growth and reduced cell death
- nonlethal genetic damage (or mutations) - acquired e.g. chemicals, radiation, viruses or inherited in the germ line
- targets of genetic damage (or mutations)- growth promoting protooncogenes, growth inhibiting tumor suppressor genes, genes that regulate apoptosis or cell death, genes that repair damaged DNA
4
Q
Adenoma Carcinoma Sequence in Colorectal Carcinogenesis
A
- Normal colon- germline (inherited) or somatic (acquired) mutations of cancer suppressor genes (first hit), APC at 5q21, mismatch repair genes, MSH2 at 2p22
- mucosa at risk- methylation abnormalities, inactivation of normal alleles (second hit), APC, B-calenin, MSH2
- adenomas- protooncogene mutation, K-ras at 12p12 and then homozygous loss of additional cancer suppressor genes- p53 at 17p13 LOH at 18q21
- carcinoma- additional mutations, gross chromosomal alterations- many genes
5
Q
Clonal Evolution of Tumors and Tumor Heterogeneity
A
- all tumors arise from a single transformed clone
- new subclones arise from the descendants of the original clone during continuous growth
- new subclones differ from the original clone in many respects- more aggressive, metastatic and acquire the ability to evade host defense
6
Q
Clonal Evolution vs Cancer Stem Cells?
A
- cancer stem cells: a sub population of cells with ability to self-renew and differentiate-have cancer initiating potential
- several issues unclear
- origin of cancer stem cells?
7
Q
Rate of Tumor Growth
A
- it takes about 30 population doublings to 10^9 cells
- in the case of a solid tumor, these many cells weigh about 1 gm, which would be the smallest clinically detectable mass
- ten more doublings would give to 10^12 and a massage of about 1kg
- one kg is the maximal solid tumor mass that is compatible with life
- it would take 90 days to generate a mass of 1gm of 30 population doubles and a cell cycle time of 3 days
- there is actually a long latent peroid before a tumor can be detected in clinic
- when a solid tumor is clinically detected, it has already completed a major portion of its life cycle
- once clincally detectable, the average volume-doubling time could be 2 to 3 months for some tumors such as lung and colon cancers
8
Q
Approaches to Cancer Treatment
A
- conventional chemotherapy- conventional chemotherapeutic agents currently in use
- molecular targeted therapy
9
Q
Conventional chemotherapy agents
A
- Alkylating Agents- Cyclophosphamide, Melphalen, Carmustine
- Antimetabolites- 5-fluorouracil, Gemcitabine, 6-mercaptopurine
- Natural Products- Vincristine, Paclitazel, Etoposide, Doxorubicin, Interferon-alpha
- Miscellaneous Agents- Cisplatin, Carboplatin, Hydroxyurea, Mitoxantrone
- Hormones and Antagonists- Prednisone, Hydorxyprogesterone, Estradiol, Tamoxifen, Flutamide
10
Q
Molecular Targeted Therapy
A
- rational molecular-based approaches in the discovery, design and utility of anticancer agents
- anticancer drugs recently approved by the FDA
- investigational drugs currently in clinical trials
11
Q
Cell Cycle and Apoptosis
A
- anticancer agents mediate their effects by inducing cell cycle arrest and/or cell death (apoptosis)
- certain drugs act in specific phase of the cell cycle while others are phase nonspecific
- a better understanding of cell-cycle kinetics and apoptosis is essential for effective utility of anticancer agents
12
Q
Cell Cycle Control
A
- cell cycle is divided into 4 phases: G1, S, G2, and M
- a normal somatic cell may spend: 6-12 hours in G1, 6-8 hours in S, 3-4 hours in G2, 1 hour in M (timing could vary depending on cell type)
- GO- post mitotic cells exit the cell cycle and enter into a non-proliferative phase e.g. terminally differentiated nerve cells, or some cells that enter temporarily into Go for weeks, months or years and later re-enter the cycle
13
Q
Two Major Types of Proteins that Control the Cell Cycle
A
- cyclins: the regulatory proteins e.g cyclins A, B, D, E
- cyclin-dependent kinases (Cdks): the catalytic proteins- Cdks 1,2,4, or 6
14
Q
How does cyclins and Cdks function?
A
- cyclin-cdk function as heterodimers that phosphorylate target proteins
- Cdks no kinase activity unless associated with a cyclin
- cyclin determines which proteins to be phosphorylated by the cyclin-Cdk complex
15
Q
Cyclin and CDk complexes
A
- each Cdk can associate with different cyclins
- different cyclin-Cdk complexes function in different phases of the cell cycle
- Cdk4-cyclin D in G1phase
- Cdk2-cyclin A in S phase
- Cdk1-cyclin B in G2/M
16
Q
Rb-E2F Pathway: progression from G1 to S phase
A
- cyclin D/Cdk4, cyclin D/Cdk6 and Cyclin E/Cdk2 phosphorylate the retinoblastoma protein
- hypophosphorylated Rb is bound to E2F family of transcription facotrs
- hyperphosphorylation of Rb results in the release of E2F
- E2F activates the transcription of genes whose products control progression from G1 to S phase
17
Q
Progression from S phase to G phase
A
-involves Cyclin A/Cdk2 but the targets remain unknown
18
Q
Progression from G2 to M phase
A
-involves Cyclin B/Cdk1 and there are several target proteins
19
Q
Checkpoint Concept
A
- mechanisms that control cell cycle progression implement checkpoints to ensure that each stage of the cell cycle is properly completeted before the next stage is initiated
- G1 arrest, S-phase arrest, G2 arrest, M arrest
- if DNA is damaged, cells will arrest in G1 or G2, no progress to S or M phases respectively
- if DNA is not properly replicated, S phase arrest and no progress to G2
- if improper spindle formation, M phase arrest
20
Q
p53 and cell cycle arrest
A
- anticancer drugs- activate p53
- activate p21 which leads to G1 or G2 Arrest
- activate 14-3-3 leads to G2 arrest
- tumors with p53 mutations; lack of G1 and/or G2 checkpoints. Altered sensitivity to anticancer drugs. Decisions about tumor response to chemotherapy
21
Q
Pathways of Cell Death (Apoptosis)
A
- cell death or cell suicide is also known as apoptosis
- it is a physiological process but can be induced e.g. by anticancer drugs
- a well controlled process that leads to cell death via a series of well-defined morphological, molecular and biochemical changes
22
Q
Morphological Changes in Apoptosis
A
- cell shrinkage
- cell shape changes
- cytoplasmic condensation
- alterations in nuclear envelop and nuclear shrinkage
- nuclear chromatin condensation and fragmentation
- cell membrane blebbing
- formation of apoptotic bodies
- cell detachment
- phagocytosis of apoptotic bodies
23
Q
Molecular and Biochemical changes in apoptosis
A
- activation of proteases: caspases and serine proteases
- proteolysis: cleavage of important proteins involved in cell structure and function
- DNA fragmentation: nucleases
- loss of mitochondrial membrane potential
- cytochrome C release from mitochondrial into cytosol
- other changes
24
Q
Caspases
A
- integral component of apoptotic machinery
- 14 caspases have been identified but 11 as well-studied
- they are cystein proteases and exist as inactive pro-enzymes named pro-caspases
- activated in response to apoptotic insults e.g. anticancer drug treatment
- they recognize specific cleavage sites within proteins (including caspases)
25
Q
How Caspases are utilized in mediating apoptosis
A
- they are utilized in cascade as Caspase Cascade
- for example, upstream initiator caspases (caspase 8 or 9( cleave and activate downstream effector (executioner) caspases such as 3, 6 and 7
26
Q
Two major apoptotic pathway
A
- death receptor-dependent pathway
- mitochondrial pathway
27
Q
Anticancer Drug Resistance
A
-resistance to anticancer drugs: intrinsic or acquired
28
Q
Intrinstic Resistance
A
- dysregulation of one or both apoptotic pathways due to: inactivation of apoptosis promoting genes/proteins (mutations, deletions or epigenetic mechanisms
- hyperactivity of survival or anti-apoptotic genes/proteins (such dysregulation in apoptotic/survival pathways, common in many cancer types, confers upon cancer cells in the intrinsic survival advantage and resistance to anticancer drugs “double whammy”)
- host factors: poor absorption or rapid metabolism or excretion ofdrugs: low serum levels. Delivery failure eg bulky tumors or high molecular mass of drugs such as monoclonal antibodies
29
Q
Acquired Resistance
A
- acquired drug resistance due to dysregulation of one or both apoptotic pathways during chemo
- many anticancer drugs induce DNA damage. During the course of chemotherapy, many cancer cells acquire the ability to rapidly and efficently repair DNA damage. Consequence: reduced apoptosis
- gene amplification: amplification of genes triggering overproduction of proteins that make anticancer drugs ineffective
- increased expression of energy-dependent efflux pumps that confer multidrugresistance by ejecting drugs out of cells. Transporters of the ATP-binding cassette (ABC) family e.g. p-glycoprotein also known as p-gp or multidrug transporter, MRP1 through MRP6 (multidrug ressitance associated protein) and some other less well characterized transporters
- decreased drug uptake because the protein molecules that facilitate drug transport inside the cells stop working
- dysregulation in drug metabolism: some drugs are normally metabolized into active metabolites inside the cells but cancer cells can acquire mechanisms to block drug activation
- acquistion of mechanisms by the cancer cells to inactivate drugs
30
Q
Anticancer Drug Toxicities-
A
- most anticancer drugs affect rapidly dividing normal and malignant cells; consequently the toxicities are associated with bone marrow, intestinal epithelium etc.
- acute toxicities are generally dose limiting
31
Q
Toxic Effect on Hematopoietic System
A
- bone marrow suppression
- suppression of all blood elements can occur
- myelosuppression- leukopenia
- G-CSF (granulocyte colony-stimulating factor) is now given to shorten the period of Leukopenia
32
Q
Toxic Effect on Dividing Mucosal Cells
A
- oral mucosal ulceration
- intestinal denudation
33
Q
Toxic effect on hair follicles-
A
-alopecia
34
Q
Toxic Effect on Reproductive System
A
- permanent Amenorrhea (females)
- azoospermia (males)
35
Q
Delayed Toxicities
A
- organ damage (heart, lungs, kidneys or liver)
- pulmonary fibrosis
- endothelial damage giving rise to venooclusive disease of liver
- nephrotoxicity giving rise to renal failure
- neurotoxicities giving rise to seizures, paralysis and coma
- major organ damage can be avoided by strict adherence to the treatment protocols
- secondary neoplasia: most alkylating agents are leukemogenic
- some drugs have specific acute effect on major organs: for example, cyclophosphamide releases nephrotoxic and urotoxic metabolite that causes hemorrhagic cystitis, anthracycline antibiotics such as doxorubicin cause dose-related cardiac toxicity
