Carcinogenesis and Chemotherapy Flashcards
What is the greatest cancer risk?
Aging
What is the transformation of normal tissue into cancer cells called?
carcinogenesis
What are four sources of carcinogenesis?
- Natural radiation (cosmic, radon) 2. Environmental (benzopyrene in cigarette smoke, nitrates in good old hot dogs)
- Viral transformation (Hep B risk for liver cancer, HPV to cervical cancer)
- Spontaneous (immune failure)
What is the mechanism for carcinogenesis?
Normal gene function transforms Suppressor genes subverted
Telomerase immortalize the bad cells
Proto-oncogenes converted to oncogenes by mutations is an example of what?
transformation of normal gene function in carcinogenesis
What is the name for the protective suppressor genes that get subverted in carcinogenesis?
Anti-oncogenes
What is the two step process of carcinogenesis and is the order important?
- Initiation (mutational injury)
- Promotion (clonal expansion of injured cells)
Initiation before promotion is critical
How is a tumor cell different and the same as its host cell?
Different because mechanixm of growth control is absent.
Same biochemically to host tissue from which the tumor derived
Is tumor cell growth endocrine or autocrine?
Autocrine, from growth factors secreted by itself
What usually kills the patient?
The invasiveness of the tumor.
Is the tumor fed from the same supply as the tissue it invades?
No, require independent nutrient/ O2 supply
What are the three primary approaches for management of cancer?
- Surgery
- Radiation
- Chemotherapy
What is usually the first step for cancer treatment?
Surgical resection to decrease tumor burden
What treatment is indicated for control of regional micrometastases and unresectable lesions?
Radiation
Radiation and surgery both require what for treatment?
Tumor localization
What is the treatment used for the systemic treatment of micrometastatic disease in other organs which can be used without surgery and radiation or in conjunction with surgery and radiation?
Chemotherapy
What is the term for chemotherapy accompanying surgery and radiation?
Adjuvant therapy
When is patient considered cured of cancer?
When 5 year disease free
What does complete response/remission mean?
tumors gone
What does partial response/ partial remission mean?
Tumor shrunk 50%
What does “stable disease” mean with regards to cancer?
The tumor is neither growing nor shrinking
What does “progressive disease” mean?
The tumor is growing
After non-curative therapy, what is the character of the cancer once it returns?
Resistant to therapy
What are the three chemotherapy regimens?
- Induction therapy
- Consolidation therapy
- Maintenance therapy
What is the term for chemotherapy that seeks rapid reduction in tumor cell burden?
Induction therapy
What is the term for chemotherapy that seeks to complete or extend initial remission?
Consolidation therapy
What is the term for chemotherapy that seeks to sustain the remission for as long as possible?
Maintenance therapy
Watch and wait therapy is used mainly for what cancer type?
Slow growing cancer: leukemia, lymphoma, prostate
Why is watch and wait therapy used on slow growing cancers?
The patient’s immune response may win Tumor is so slow growing, cancer drugs can’t target it
The side Effects may outweigh benefits
What are three risks associated with delaying cancer treatment?
Patients emotional well-being
Cancer may spread or transform rapidly Decrease likelihood of complete remission
What is the ideal goal of cancer chemotherapy?
Eliminate all of tumor cell population with limited toxicity to patient
A given concentration of drug, applied for a defined period of time, will kill a constant fraction of the cell population, independent of the number of cells is known as what?
Fractional cell kill hypothesis
For a log kill of 2, which reduces the tumor cell number from 109 to 107, what percentage of the cell population must be killed?
99%
What log kill is required to kill the total cell population?
Log Kill 9
What is assumed with lower log kill numbers?
Immune system takes over to eradicate remaining cells
What phase of the cell cycle do anti-neoplastic drugs focus on?
S-phase, M-phase
What is occurring in S-phase?
DNA synthesis
What is occurring in M-phase?
Cell division
Of the S and M phases, which one is the major drug target?
S-phase
Cells within solid tumors are normally in what phase?
G0 – dormant, insensitive to drugs
What is a good thing about surgery or radiation that might aid chemotherapy?
Can recruit cells out of G0 back into active growth so they will be susceptible to drugs
What is the clonal origin theory of tumors?
Every malignancy starts from 1 cell then forms a colony, that through mutations becomes heterogenous
Why does the heterogeneity of tumor cells cause problems in treatment?
It makes them hard to target. One cell might have an efflux pump whil another cell is metabolically inactive.
What is the problem when designing a cancer chemotherapy regimen?
cancer drugs have narrow therapeutic index which restricts simply increasing the dose
What is a major type of resistance to cancer chemotherapy?
Multi-drug resistant pumps
Why are liver cancers hard to treat (example of drug resistance of cancer)?
Liver cancer can enhance drug inactivation via the liver glutathione redox pathway
What are nine ways cancer can be resistant?
- Alter drug transport
- Alter level or sensitivity of cell targets
- Limited drug activation
- Enhanced drug inactivation
- Competition by endogenous substrates 6. Inability to undergo apoptosis
- Mutations in growth arresting genes
- Enhanced DNA repair
- Autophagy
What method can be used to circumvent cancer chemotherapy resistance?
combination chemotherapy (but this is susceptible to multi-drug resistant phenotype)
Multi-drug resistant phenotype cancer s recognize what and pump it out?
large lipophylic naturally derived cancer drugs
What are 5 types of cytotoxic drugs?
- Alkylating agents
- Antimetabolites
- Antitumor antibodies
- Mitotic inhibitors
- Topoisomerase inhibitors
Antimetabolites are analogues of what?
Natural substances or reaction intermediates
Antimetabolites attack what cell cycle phase and do what?
Require metabolic activation then attack S-Phase to interfere with DNA synthesis
Topoisomerase poisons are derived from what and do they require metabolic activation?
Natural (plant or bacteria). Do not require metabolic activation.
Are topoisomerases cell cycle specific and how do they act?
Not cell-cycle specific, but active in the cell cycle. Promotes DNA strand breaks.
Microtubule poisons are derived from what and active in what phase of the cell cycle, and do they require metabolic activation?
They are natural products, active in M-phase, and do not require metabolic activation
Microtubule poisons act where in cancer cell?
interfere with microtubule function
From what are alkylating agents derived?
They are chemically synthesized. First group of anti-tumor drugs.
What are 2 types of alkylating agents?
Bifunction (DNA cross linkers)
Monofunction (DNA damager)
Are alkylating agents cell cycle specific?
No
What is a toxicity associated with alkylating agent usage?
Secondary malignancies
Chemotherapy is toxic to what host tissues?
High growth fraction tissues Bone marrow Skin Hair follicles GI Sperm
Of the high growth fraction tissues, which one is the dose limiter for chemotherapy?
Bone marrow
What are the major chemotherapy side effects?
Nausea Stomatitis Alopecia Bone marrow suppression Organ toxicity
When should chemo start?
Low tumor burden when growth fraction high
How should chemotherapy be dosed?
Dose to maximum toxicity before changing therapy
Should toxicity ever exceed therapeutic benefit?
No
How to design combo therapy to obtain total cancer cell killing?
Use drugs with differing toxicity profiles, differing mechanisms of action, synergistic, and who don’t have common resistance
What is the principle for cancer chemotherapy dosing?
Highest dose possible repeating does as frequently as tolerable
Why treat cancer early?
- Less metastases
- More S-phase cells
- More homogenous tumor
- Fewer resistant tumor cells
- Patient is healthier
What is problem with animal testing cancer drugs?
It’s a mouse tumor(murine) or a human tumor in an immunosuppresed mouse, so it is not a direct correlation
What is asked of a new cancer drug in phase III of human trials?
I”s the drug better than what is currently available”?
