Pharm cancer I. Flashcards
How many new cases of cancer a year? How many deaths due to cancer a year? (in the US)
1,000,000 new cases, 500,000 deaths
What is cancer characterized by?
abnormal cellular growth and reduced cell death
What are targets of genetic damage (or mutations)
- growth promoting protooncogenes 2. growth-inhibiting tumor suppressor genes 3. genes that regulate apoptosis or cell death 4. genes that repair damaged DNA
What drives tumorigenesis?
sequential alterations (mutations) in 2-8 driver genes conferring selective growth advantage
passenger gene mutation
mutations in tumors in additional genes by do not confer growth advantage
driver genes
linked to cell fate determination, cell survival, and genome maintenance
clonal evolution of tumors
all tumors are believed to arise from a single transformed clone —> get new subclones become more aggressive, metastatic and ability to evade host defense
cancer stem cells
sub-population of cells with ability to self-renew and differentiate have cancer initiating potential
What are examples of conventional chemotherapeutic agents?
alkylating agents, antimetabolites, natural products, miscellaneous agents, hormones and antagonists
alkylating agents
nitrogen mustard, ethylenimines & methylmelamines, alkyl sulfonates, nitrosoureas, triazenes
antimetabolites
purine and pyrimidine analogs
natural products
vinca alkaloids, taxanes, epipodophylotoxins, camptothecins, antibiotics, enzymes, biological response modifiers
anticancer agents: how do they work?
induce cell cycle arrest or cell death
normal cell cycle
G1, S, G2, M (sometimes G0 - post mitotic cells exit the cell cycle and enter non-proliferative phase)
What two proteins control cell cycle progression?
cyclines (regulatory proteins A, B, D, E) and cyclin-dependent kinases (Cdks) catalytic proteins 1,2,4,6
How do cyclin and cdk function?
as heterodimers that phosphorylate target proteins - CDKs have no kinase activity unless associated witha cyclin
What does the cyclin determine?
which proteins would get phosphorylated
What cyclin-cdk complex functions for G1 phase?
cdk4-cyclin D, cdk6-cyclin D, and cdk2-cyclinE
What cyclin-cdk complex functions for S phase?
cdk2-cyclin A
What cyclin-cdk complex functions for G2/M phase?
cdk1-cyclin B and cdk1-cyclin A
What do cyclinD-cdk4, cyclinD-cdk6, and cyclinE-cdk2 phosphorylate?
Rb
Rb does what when hypophosphorylated and what when hyperphosphorylated?
hypo: bound to E2F; hyper: release of E2F (causes conformation change)
E2F
activates the transcription of genes whose products control progression from G1 to S phase
If DNA is damaged in a normal cell….
cell will arrest in G1 or G2
If DNA is not properly replicated….
S phase will arrest
If there is improper spindle formation….
M phase arrest
What morphological changes happen in apoptosis?
cell shrinkage, shape change, cytoplasmic condensation, alterations in nuclear envelop and nuclear shrinkage, nuclear chromatin condensation and fragmentation, cell membrane blebbing, formation of apoptotic bodies, cell detachment, phagocytosis of apoptotic bodies
What activates proteases in an apoptotic cell?
caspases and serine proteases
proteolysis
cleavage of important proteins involved in cell structure and function
DNA fragmentation is done by what?
nucleases
What is released from mitochondria in apoptotic cells?
cytochrome C
caspases
integral component of apoptotic machinery - exist has inactive pro-enzymes, activated in response to apoptotic insults, recognize specific cleavage sites within proteins
What are the 2 apoptotic pathways?
death receptor-dependent pathway and mitochondrial pathway
intrinsic resistance
- dysregulation of one or both apoptotic pathways common in many types of cancer and occur due to: inactivation of apoptosis promoting genes/proteins (mutations, deletions, epigenetic mechanisms) 2. hyperactivity of survival or anti=apoptotic genes 3. host factors (poor absorption, rapid metabolism//excretion, delivery failure)
acquire resistance
dysregulation of one or both apoptotic pathways during chemotherapy - durin the course of chemo, many cancer cells acquire the ability to rapidly and efficiently repair DNA damage
p-gp
multidrug transport (MRP1-MRP6 = multidrug resistance associated protein)
What are toxic effects of anticancer drugs?
bone marrow suppression, oral mucosal ulceration, intestinal denudation, alopecia, permanent amenorrhea, azoospermia)
What toxic effect do alkylating agents have on the body?
reproductive system toxicity - most are also leukemogenic
How can major organ damage by avoided with anticancer drugs?
strict adherence to treatment protocols
Which drug causes hemorrhagic cystitis?
cyclophosphamide
