Lecture 4: Select General Concepts in Oncology

What is the "name of the game" in cancer chemotherapy?

selective killing or toxicity to kill cancer cells and not normal healthy cells

Normal healthy cells divide only ______ ______ and are controlled by growth ______ and cell cycle ______

when needed; signals; checkpoints

Cancer cells divide ______ by ignoring normal cell cycle regulation and can actually ______ checkpoints in the cell cycole

uncontrollably; bypass

When normal healthy cells become damaged or too old, they will eventually undergo ______

apoptosis

Even when cancer cells are severely damaged, they can ______ ______

avoid apoptosis

DNA in normal healthy cells is ______ and most errors and damage can be fixed by DNA ______ ______. They also have ______ mutation rates

stable; repair systems; low

Cancer cells have defective DNA repair mechanisms leading to ______ ______ which can accumulate ______ in genes that control cell growth, repair, and death

genomic instability; mutations

Within a cancer cell, some anticancer drugs can ______ DNA, which causes desired cancer cell ______

damage; apoptosis

Normal healthy cells interact with the human immune system by displaying "______ ______" proteins that are typically ignored by the immune system

normal self

Cancer cells can express ______ proteins which can ______ detection by the human immune system by suppressing certain immune responses or "disguising themselves"

abnormal; evade

We need to consider the ______ of cell growth and cell division between cancer cells and normal healthy cells

rate

Normal healthy cells grow/repair ______

slow

Cancer cells grow/repair ______

fast

The rate of cell growth and cell division leads to some anti-cancer drugs displaying ______ ______ for killing or being more toxic to cancer cells versus normal healthy cells via the "______ ______ ______ ______ ______"

enhanced selectivity; rate theory of cancer chemotherapy

Traditional cytotoxic chemotherapy preferentially damages what?

actively proliferating/dividing cells

Many types of cancer cells divide ______, but some normal cells also divide this way

rapidly

Therefore, traditional cytotoxic chemotherapy often has ______ ______ ______

limited cell-type selectivity

Which normal tissues are most susceptible to traditional cytotoxic chemotherapy?

normal tissues with rapidly dividing normal cells like GI epithelium, hair follicles, and bone marrow

What can traditional cytotoxic chemotherapy do to GI epithelium?

mucositis, nausea, diarrhea

What can traditional cytotoxic chemotherapy do to hair follicles?

alopecia

What can traditional cytotoxic chemotherapy do to bone marrow?

myelosuppression

With traditional cytotoxic chemotherapy, normal tissues that undergo rapid cell division are ______ damage, but they are ______ toxicities

collateral; predictable

What are the clinical consequences of bone marrow suppression/myelosuppression?

decreased leukocytes, erythrocytes, and blood platelets

What does decreased leukocytes cause?

infections

What does decreased erythrocytes cause?

anemia

What does decreased blood platelets cause?

bleeding

Traditional cancer chemotherapy exploits ______ cell division, affects both ______ and ______ dividing cells, and ______ often reflect damage to normal rapidly dividing tissues

rapid; cancer; rapidly; toxicities

Targeted anti-cancer drugs exploit a ______ molecular target, are usually more ______ for cancer-associated pathways, and toxicities depend on the specific ______ or ______

specific; selective; target; pathway

Why must we know whether a patient's tumor expresses the target?

no target means the targeted drug would yield little to not expected benefit

Why are biomarkers important in cancer treatment?

with tumor biomarkers, the treatment can identify a therapeutic drug target and helps to select the appropriate drug

Targeted anti-cancer drugs DOES NOT MEAN ______ free

toxicity

Targeted anti-cancer drugs DOES MEAN ______ ______ ______

greater molecular selectivity

Why might 2-3 anticancer drugs work better than just one anti-cancer drug?

increased tumor kill, decrease drug resistance, increase drug synergy

What makes a good anti-cancer drug combination?

rational balance with different mechanisms of action, non-overlapping drug resistance mechanisms, non-overlapping drug toxicities, and proper dosing sequence or schedule

Using different mechanisms of action attacks through ______ pathways

complimentary

Non-overlapping drug resistance mechanisms helps resistant drug ______ less likely

clones

Non-overlapping drug toxicities is important because it helps avoid the same ______ ______

dose-limiting toxicity

Proper dosing sequence or schedule is calculated by using PK/PD and ______ biology intelligently

cell-cycle

What occurs with synergistic anticancer drug therapy?

increased tumor kill

What occurs with redundant anticancer drug therapy?

no additional efficacy

What occurs with harmful anticancer drug therapy?

increased patient harm

The goal of anticancer therapy is to maximize ______ ______ without proportionally increasing ______ ______

tumor kill; patient harm

What parts of the cell cycle are important when treating cancer?

DNA synthesis, G0 phase, Mitosis

What occurs in the DNA synthesis phase (S Phase)?

DNA replication occurs

What occurs in the G0 phase (resting phase)?

cells are alive but not actively dividing and they can re-enter the cell cycle whenever they need to divide again

What occurs in mitosis (M phase)?

the cell divides into two daughter cells

Cancer causes a ______, ______ cell cycle

uncontrolled; unregulated

Cancer cells lose checkpoint control, proliferate continuously, and spend more time in cell cycle phases which makes cancer cells more vulnerable to anti-cancer drugs that target ______ ______

cell division

What are cell cycle-specific (CCS) drugs?

act only on cancer cells that are in a specific phase of the cell cycle

What are cell cycle-non-specific (CCNS) drugs?

can damage or kill cancer cells regardless of the cell cycle phase

Can cell cycle-specific (CCS) drugs damage or kill cells in G0?

no

Can cell cycle-non-specific (CCNS) drugs damange or kill cells in G0?

yes

What are some examples of CCS drugs in S-phase?

anti-metabolites

What are some examples of CCS drugs in M-phase?

vinea alkaloids and taxanes

What are some examples of CCNS drugs?

DNA alkylating agents and piatinating agents and anthracyclines

CCS drugs are most effective against ______ ______ ______. Why?

rapidly dividing tumors; because many cancer cells are passing through the vulnerable phase

With CCS drugs, ______ or ______ dosing schedules are needed to maximize chances of hitting cancer cells at the right phase

prolonged; frequent

Since fewer cancer cells are in a vulnerable phase at any given time, CCS drugs are ______ effective against slow growing tumors

slow

CCNS drugs can kill ______ and ______ cancer cells

dividing; non-dividing

CCNS drugs are useful against ______ ______ ______ or tumors with many cancer cells in the ______ phase

slow growing tumors; resting

Since the actions of CCNS drugs is not tied to a specific cell-cycle window, how are they often given?

larger single doses or less frequently

CCS drugs are generally described as what?

schedule-dependent

What does schedule-dependent mean?

both the timing and the duration of drug administration matter in addition to the drug dose

CCNS drugs are generally described as being what?

dose-dependent

What does dose-dependent mean?

drug dose tends to matter more than drug scheduling

What type of growth-fraction tumor cells are being eliminated with CCS drugs?

high growth-fraction tumor cells are eliminated because most of the cancer cells are not in G0

What type of growth-fraction tumor cells are being eliminated with CCNS drugs?

both high and low growth-fraction tumor cells

What are CCS drugs best for?

rapidly dividing tumors

What are CCNS drugs best for?

both rapid and slow dividing tumors

What is a major limitation of CCS drugs?

ineffective if the tumor grows slowly or many of the cancer cells are in G0

What is a major limitation of CCNS drugs?

may cause more general toxicity to normal tissues

What type of drugs can work in the resting phase?

CCNS drugs where DNA can be the target

What type of drugs can work in the S-phase?

CCS drugs like anti-metabolites that may target enzymes involved in DNA synthesis

What type of drugs can work in the M-phase?

CCS drugs like anti-mitotics that may target microtubules

The log-kill hypothesis is chemotherapy that kills a constant ______ and NOT a constant ______ of susceptible cancer cells

fraction; number

What is the lower limit of cancer cell detection?

one billion cells

Why might a CCNS drug be given before a CCS drug?

the concept of recruitment

Why would we administer the CCNS drug first and then a CCS drug second?

administer CCNS drug first to achieve a significant log kill which will cause cancer cells in G0 that were not killed by the CCNS drug to be recruited back into the cell cycle and then the CCS drug can be administered to kill the actively dividing cancer cells

When would you want to avoid the "recruitment dosing schedule"?

situations where the CCNS drug would prevent the elimination of the CCS drug

Does the order of anticancer drugs matter?

Yes

Recruitment is a pharmacologic ______ not a ______ ______ for sequencing chemotherapy. Actual regimens follow ______-______ schedules

rationale; universal rule; evidence-based

The MOA of an anticancer drug is not trivial, it is the starting point for ______ what happens to the patient

predicting

What can we predict when we know the MOA of an anticancer drug?

toxicity, monitoring parameters, patient care

If you know the MOA of an anticancer drug, the rest of the drug becomes more ______!!

logical

Each treatment kills a fraction of susceptible tumor cells = ______ ______

log kill

Surviving resting cancer cells may re-enter the cell cycle = ______

recruitment

Normal tissues need time to recover between treatments = ______

recovery

What are the 5 questions every pharmacist should ask about any anticancer drug?

what is the drug target or MOA, which normal cells will also be affected, what toxicities does the mechanism predict, how should the patient be monitored and counseled, how does this drug fitinto the overall treatment strategy