Compare and Contrast oncogenes and tumor supressors
Oncogenes are genes that positively influence tumor formation (ras)
Tumor supressors are genes that negatively impact tumor growth (p53)
Some cancers affect the cell cycle. Discuss
proteins or pathways involved in regulating the checkpoints between the phases of the cell cycle may be absent or mutated which can lead to uncontrolled and unregulated cell cycle proliferation
Certain drugs will target the cell cycle to help reduce this proliferation (cell-cycle specific)
Activation of oncogenes overrides what part of the cell cycle?
Inactivation of tumor suppressor genes overrides what part of the cell cycle?
overrides G1 arrest
Overrides G2 arrest
Now the cell isn't arrested when it should be, and can cause cancer
What is primary chemotherapy?
chemotherapy that is given as the primary treatment
used for advanced cancers with no other alt. tx or advanced metastatic disease
What is the goal of primary chemotherapy?
relieve tumor related symptoms
improve quality of life
prolong time to tumor progession
In what cancers or patients can primary chemotherapy be curative?
HL and NHL, choriocarcinoma, germ cell cancer, and AML
Burkitt's lymphoma, Wilm's tumor, Embryonal rhabdomyosarcoma, ALL
What is neoadjuvant chemotherapy
chemo that is given for a localized cancer in which alternative therapies exist but are less than completely affective
What is the goal of neoadjuvant therapy?
reduce the size of the tumor to make surgery easier/spare normal organs
typically given after surgery as well (becomes adjuvant therapy at that point)
What is adjuvant chemotherapy?
chemo used as an adjuvant (or help) to local therapy and administered after surgery has been preformed
What is the goal of adjuvant therapy?
reduce the incidence of local and systemic recurrence
improve the overall survival
effective at prolonging dz-free state and survival
What is growth fraction?
ratio of cell proliferation to G0 cells
this is the major determinant of a cancer's responsiveness to chemotherapy
antineoplastics will be more effective on cells with a high growth fraction and will impact noncancerous high growth cells
What are normal body cells with high growth fraction?
cells of the bone marrow, GI, hair, sperm forming cells
Solid tumors can be difficult to treat because of what rule?
the growth fraction
the initial rate of growth is fast, but decreases overtime, such that by the time it is detected, it is no longer proliferating as rapidly, thus certain drugs won't be as effective
Ex: burkitt's lymphoma with high growth fraction, easier to cure with chemo, vs. colorectal carcinoma with a low growth fraction, chemo has a minor effect
Note, surgery/rad increase growth fraction which can increase chemo efficacy!
What is the log cell kill hypothesis?
antineoplastic therapy follows first-order kinetics: a given dose of drug destroys a constant fraction of cells
log cell kill hypothesis states that antineoplastic agents kill a fraction of cells rather than an absolute number per dose
therefore, only a limited log cell kill can be expected with each individual treatment
Why are antineoplastic agents delivered in a staggered/intermittent schedule?
high dose intermittent therapy allows recovery of normal, healthy tissues
agents given as constant infusions can include those that are rapidly metabolized or excreted as well as those that are cell cycle specific
What are some various routes of administration?
What are pharmacologic sanctuaries?
intracavity, intrathetcal, intraventricular, intraarterial, topical, isolated limb
pharmacologic sanctuaries are regions where tumor cells are hard to reach (CNS)
What is combination chemotherapy?
it is the use of multiple agents, more successful than single agent regimens
1. provides max cell killing within tolerated toxicity
2. effective against broader range of cell lines with heterogenous population
3. may delay or prevent drug resistant tumors
What are the 5 principles used in the design of combination chemotherapy regimens?
1. each drug should have some individual therapeutic activity
2. drugs that act by diff. mechanisms should net an increased log cell kill and decrease drug resistance
3. drugs with different dose-limiting toxicities should be used in combination to avoid organ damage
4. intensive intermittent treatment schedules should allow time for recovery in between
5. several cycles of treatment should be given (6-8)
What are two primary(inherent) chemotherapy resistances?
drug resistance in the absence of prior exposure to available drugs
genomic instability of the cancer like p53 mutations
What are acquired chemotherapeutic drug resistances?
What are some examples?
develops after exposure to a cancer drug
gene amplification or supression
decreased drug transport into the cell
reduced affinity of target
increased expression of enzyme that causes inactivation
increased expression of DNA repair enzymes
It is worth noting that exposure to chemo drugs can increase what?
increase the cancer heterogeneity, causing it to become less monoclonal and more difficult to treat and can become resistant to treatment
What is important about p-Glycoprotein?
To what kind of antineoplastics is there a high resistance to?
PGP expression is found in tissues with barrier functions (kidney, liver, GI) and BBB/PBB
a high baseline expression of PGP correlates with high primary resistance to natural products
if PGP is overexpressed, can lead to acquired drug resistance
What are common antineoplastic drug toxicities
death of rapidly proliferating normal cells
sperm forming cells
(many of these drugs can damage so much that they cause cancer later in life-alkylating agents)
Common adverse effects of antineoplastics?
myelosupression (dif. wound healing, increased infections)
low sperm count/azospermia
depressed development in children
How to minimize adverse effects of antineoplastics?
choose the route of administration with as little systemic toxicity
use of other pharm agents to decrease adverse effects (hemopoeitic agents, Zofran, bisphosphonates)
rest and recovery between doses
What are the five major types of alkylating agents?
1. cyclophsphamide (N mustard)
2. carmustine (Nitrosoureas)
3. busulfan (alkyl sulfonates)
4. procarbazine (methylhydrazine)
5. dacarbazine (triazines)
also included is cisplatin, a platinum compound
What is the most widely used alkylating agent?
(most vomiting, too)
Alkylating agents are cell cycle (specific or nonspecific)?
What is the MOA of alkylating agents?
alkylating agents form covalent links between DNA of between guanine which prevents unwinding of the DNA (and thus prevents replication)
How is cyclophosphamide activated?
What are two cytotoxic products?
Which one causes hemorrhagic cystitis?
How is it treated?
Must past through CYP2B and hepatic cytochrome oxidase and hepatic aldehyde oxidase to become phosphoramide mustard (cytotoxic) and acrolein (cytotoxic)
Acrolein causes hem. cystitis
Mesna inactivates acrolein and is used prophylactically