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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 

implantable wafers

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 

bone marrow

GI tract

hair follicles

oral mucosa

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