Science of Antineoplastic Drugs Flashcards
What are the key strategies being emphasized for new drug development?
- New mechanisms of action
- Monoclonal antibodies against specific cellular targets
- Drugs to modulate or reverse drug resistance
- Drugs for supportive care of pts with cancer (eg. better antiemetic therapy, hematopoietic growth factors)
What was a key turning point for chemo history?
Discovering that multiple agents can be combined to provide better outcomes
Define: Growth Fraction
The portion of cells actively cycling compared with the entire population
What can a cell do following mitosis?
- Leave the cell cycle
- Differentiate and eventually die
- Enter a resting state (G0)
- Reenter the cycle at some later time (stem cells)
- Enter the G1 phase and continue to cycle
What cell phase is typically resistant to chemo?
G0
What are the key characteristics that seperate tumor cells from normal cells?
- Loss of controlled cell division
- Lack of differentiation
- Ability to invade surrounding tissues and establish new growth at distant sites
What do antineoplastic drugs use as a target for their cytotoxic effects?
The rapid proliferation rate of cells. This also explains the toxicities of normal cells during tx, as they are also going through the cell cycle and dividing (although at a slower rate)
The selective effects of antineoplastic drugs on both proliferating normal and tumor cells can be explained by:
1) Tumor growth is often exponential
2) Double times vary widely depending on tumors
3) Chemo-sensitive tumors tend to grow faster than slow-growing tumors that are less responsive to chemo
Why is uncontrolled proliferation NOT the sole distinguishing trait of tumors?
The rate is not higher than what is seen in other normal renewal cells such as in the bone marrow or GI. Therefore there would be no distinction between normal and tumor cells if this were the sole character. Also tumor cells reproduce rapidly because of lost hemostatic mechanisms (eg. apoptosis), setting it apart from cells that are intended to replicate quickly.
What is the cell kill hypothesis?
- Predicts the number of cells killed based on the dose of the chemo given
- Applies only to cells that are actively proliferating because not all cells are proliferating! (G0 tumors)
What is the log phase?
When tumors have a high growth fraction and a short doubling time
What is the Gompertzian curve and how does it affect the cell-kill hypothesis?
- Tumor growth fraction and proliferation rate is not constant, but rather tends to be quick at first (the log phase) and slows down as the tumor increases in size
- Eventually reaching a plateau phase where only minimal increases in size occur (slower doubling times)
- Relevant to chemo because the response will be based on in which growth phase the tumor is in (eg. if cancer is more advanced, less cells are dividing and therefore it will be less susceptible to chemo since it targets quick replicating cells)
What are key patient factors that influence the drug-selection of different cytotoxic agents?
Wide variations in both therapeutic response and unacceptable toxicity are observed in patients receiving chemo, and this can be explained by differences in the patient themself, the chemo being given and the type of tumor
- Response to toxicity (occurrence and severity can require dose reductions or delays)
- Organ dysfunction (renal and hepatic insufficiency requires dose or schedule alterations)
- Previous treatment (may not be eligible to receive the same drug again or a drug with a similar toxicity if they previously received chemo; some drugs have maximum lifetime doses to prevent severe effects; previous bone marrow transplants or use of severely marrow-toxic drugs may preclude future use of myelosupressive drugs)
- Medical history (certain conditions, like preexisting diabetic neuropathy, require certain drugs be avoided)
- Treatment plan (if they are candidates for autologous stem cell transplant will need to avoid certain chemo drugs)
- Age
What are drug factors influence chemo response and toxicity?
- Antineoplastic activity (depends on tumor origin and intrinsic resistance)
- Pharmacokinetics (ability to reach their cellular targets; can be affected by metabolic activity, drug clearance, protein binding alteration)
- Dose
- Schedule
In addition to patient and drug factors, what else determines response to treatment?
1) Genetic instability of the tumor cell
2) Emergence of drug resistance ** - multiple types of resistance
Is drug resistance temporary or permanent?
- Can be either temporary or permanent
- Temporary usually as a result of the drug’s inability to reach target cells (poor blood supply, sites like the CNS with more limited access anatomically, altered pharmacokinetic parameters) and might be reversed by altering the delivery, dose or schedule
- Permanent is an inheritable mechanism from a genetic mutation or preexisting trait
What is the difference between primary and secondary permanent cytotoxic resistance?
Primary = prior to treatment Secondary = after exposure to antineoplastic drugs
What is the Goldie-Coldman model, and how does it explain cytotoxic drug resistance?
- Model: Chemo treatment failures allows for drug resistance, so model promotes using multiple drugs to prevent resistance
Genetic instability of tumor cells with high mitotic rate allows for emergence of resistant clones > drug resistant cells arise from random genetic mutations occurring before or during therapy > therefore a combination of chemo is often optimal and can prevent resistance
What are the different types of cytotoxic drug resistance?
1) Phenotypic drug resistance
2) Multidrug resistance
3) p53 and cell cycling
What is Phenotypic Drug resistance?
- Spontaneous genetic mutations in tumor cells that occur regularly; there is always a chance a mutation will occur and alter the sensitivity
- Timing appears to be at any time; can be before chemo, early or later in chemo
- like antibiotics, cytotoxic drugs selectively kill sensitive cells and leave behind resistance
- Because tumor cells are genetically unstable and exhibit a high rate of mutation, these mutations can result in minor effects, no effects, or a mutation that alters its sensitivity to cytotoxic drugs
What is multidrug resistance?
- Mechanisms developed by the tumor cells to protect themselves from cytotoxic affects of agents
- Produces resistance to a group of drugs that are similar of have different mechanisms
- Results may result from:
- alterations in drug metabolism and targets
- ability of cells to repair DNA lesions
- decreased intracellular drug concentrations
How does p53 and cell cycling affect resistance?
- Sensitive Ca cells are killed initially during treatment, and if they survive they develop resistance to further treatments. About ~50% of all Ca has a genetic defect of p53, and therefore if this genetic defect survives in a resistant cell it can keep reproducing unchecked.
- Those who are having poor responses to chemo and are more prone to relapse are more likely to have p53 gene mutations
What are the classifications of chemo treatments?
1) Adjuvant
2) Neoadjuvant
3) Primary
4) Induction
5) Combination
What are the role of chemo and radiotherapy protectants?
- For use in preventing or reversing drug-induced toxicities associated with anticancer drugs
- Allow for treatment that follows the preferred dosing and schedule without need for adjustment in order to provide the best outcome
What is high dose chemo with peripheral blood stem cell support?
High-dose chemo with autologous rescue peripheral blood stem cell support. Basically, this has the capacity to restore hematopoiesis without the need for bone marrow harvesting, and is now the standard of care for several blood and lymph cancers.
Describe how chemo can act as a radiation sensitizer:
- Concurrent therapies show improved results for certain groups of cancer
- Combined use may better eradicate resistant cells
- Regrowth following radiation is slowed by adding chemo
- More vulnerable to chemo
- Cytoreductive effects of chemo improves tumor oxygen supply, and therefore an increased susceptibility to radiation effects
