As cancer cells grow, what happens to their genetic stability?
It declines - they usually acquire more and more mutations. These can provide drug resistance or other virulence factors, like the ability to spread or proliferate more quickly.
A cell mass with 109 cells is usually how large?
1 cm - this is the smallest "easily detectible" mass clinically.
When we can clinically detect a mass, how easy is it to kill?
Hard - it's growth fraction has already decreased a lot.
What is a growth fraction?
The fraction of dividing cells (susceptible to chemotherapy) to all cells. Larger growth fraction usually occurs before a cancer is clinically detectable.
What's Gompertzian growth?
The idea that a population will boom until it reaches a resource choke and its rate of growth will then decline.
Drugs are more useful during which phase of tumor growth?
The exponential, usually subclinical phase.
What's adjuvant chemotherapy?
Chemo used in combo with something like radiation or surgery to eliminate micrometastases still in the exponential part of their growth.
Which tumors usually have a smaller growth fraction?
Solid tumors, like colon and lung (except small cell). Blood tumors and embryonic tumors are usually have high growth fractions.
What's a phase-specific drug?
A drug that only acts on cells during a certain phase of the cell cycle. Thus, only a certain amount of cells will be susceptible to one short infusion.
What's a phase nonspecific drug?
A drug that targets cells regardless of their cycle phase.
What's log cell kill?
Anticancer agents have first order kill effects - they generally kill a constant fraction of tumor cells, so doses must be given as frequently as manageable.
Why do we give chemotherapy in combo?
Maximizes tumor cells killed, prevents resistance to treatment regimen.
What are the characteristics of an anti-cancer drug combo?
1. single agent activity
2. different mechanism
3. adverse effects cannot overlap
What's the Goldie-Coldman hypothesis?
Cancers that divide more quickly are more likely to be drug resistant.
What's the implication of the Goldie-Coldman hypothesis?
Even small cancers are likely to have cells that are resistant to treatment, so we have to use combos.
What's intrinsic drug resistance?
Due to some intrinsic factor, a tumor is resistant to treatment by a given agent. The resistance is pre-existing.
What are examples of intrinsic resistance?
- tissue of origin confers resistance (GI, renal and p-glycopeptide)
- tumorigenesis developed resistance
- physiologic: growth is too slow, blood supply is not sufficient to deliver drugs, or privileged site
What's acquired drug resistance in cancer?
The resistant tumor came about because of treatment or further tumorigenesis. It was originally sensitive to treatment.
What are some methods of resistance to cancer drugs?
Efflux pumps or decreased uptake (methotrexate), altered target, drug metabolism, increased DNA repair, inhibition of apoptosis
What's the MDR pump?
Multi-Drug-Resistance, common in GI, renal, cancers involving BBB. These normal tissues had pump to keep stuff out and maintain balance but it's overexpressed in response to a drug, but it pumps out a lot of drugs.
To what drugs are MDR+ tumors still sensitive?
To what drugs are MDR tumors usually resistant?
vincristine, methotrexate, doxorubicin
Toxicities of anticancer drugs?
1. myelosuppression - delayed
5. second malignancies
profile depends on drug in question
Why is myelosuppression delayed?
Stem cells and maturing cells are spared, but the amplification pool is killed since it's in cycle. Thus, when the already-maturing cells die, myelosuppression is seen.
How do marrow stimulators affect cancer treatment?
We can decrease myelosuppression and get recovery faster, we can dose chemo more often and kill more cancer cells (give them less time to recover, too).
Special toxicity for cyclophosphamide?
Special toxicity for microtubule inhibitors?
Special toxicity for cisplatin?
Special toxicity for doxorubicin?
Special toxicity for bleomycin, busulfan?
dose-cumulative pulmonary fibrosis
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