Download MS2 Onc Cancer chemotherapy

4 ways chemotherapy is generally used
1. induction chemo – primary treatment for adv cancers with no alternative treatment
2. adjuvant chemo – systemic chemo, after surgery and radiation of solid tumors, to attack micrometastases
3. primary (neoadjuvant) chemo – chemo prior to surgery or radiation
4. site-directed perfusion of a specific body region affected by cancer
Goal = cure
 The disappearance of any evidence of tumor for several years and a high actuarial probability of a normal life span
 If cure is not attainable, goal = palliation
o Prolongation of life and improvement of symptoms to improve quality of life
Cancer chemotherapy generally targets cell replication, independent of whether cells are normal or neoplastic.
Tumor growth characteristics
 Cell cycle
o CCS drugs – cell cycle specific drugs
 Act on cells traversing cell cycle and inhibit cell growth at specific phases
 More effective against tumors with a higher percentage of cells that are replicating (high growth fraction)
o CCNS drugs – cell cycle non-specific drugs
 Act on cells that are resting or cycling
 Useful against solid tumors with a low percentage of replicating cells, as well as those with high growth
fractions
 Alkylating agents and most antibiotics
 Growth fraction
o Fraction of tumor cells that are progressing thru cell cycle (G1/S/G2M) influences susceptibility to most cancer
chemotherapeutic agents
o Tumors most susceptible to chemotherapy are undifferentiated and have high growth rates
 Cancer detection
o 109 cancer cells is the smallest tumor burden that is physically detected  clinical symptoms
o 1012 cells = death
o Growth fraction DECREASES with size of tumor  INCREASED when tumor burden is reduced by either surgery
or radiation
o Tumor population becomes more heterogeneous with time  increases chances of occurrence of drug-resistant cell
varients
 Log kill hypothesis
o Cytotoxic drugs act with first order kinetics (given dose kills a constant proportion of cell population)
o 99.9% killing efficiency = 3 log kill dose  tumor mass of 109 decreases to 106
o Interval treatment is done to allow bone marrow recovery to minimize normal cell toxicity
 Tumor cell heterogeneity
o Each tumor is comprised of a very heterogeneous, genetically unstable and evolving population of cells
o Produces differences in responsiveness to anti-neoplastic drugs and also facilitates the development of drug
resistance
 Toxicity of normal cells
o Major limiting factor is lack of selective toxicity for normal bone marrow cells vs cancer cells
o Killing of rapidly proliferating normal cells of buccal mucosa, GI mucosa, and hair follicles
o Adverse toxic side-effects
 Common
 Myelosuppression
o Bone marrow toxicity  destruction of actively proliferating hemoatopoietic precursor
cells
o Leucopenia and thrombocytopenia  increased risks of infections and hemorrhage,
respectively
o Time to recovery of marrow is limiting factor
o G-CSF and GM-CSF can potentially reduce neutropenia assoc with chemo  bind to
cognate cell surface receptors on BM precursor cells and stimulate growth and
differentiation of their respective cell lineages
o Reversible
 GI tract toxicity
o Stomatitis, dysphagia, diarrhea
o Reversible
 Nausea and vomiting
o

Anticipatory nausea and vomiting are experience by approx 10-44% of patients who
receive chemo  simulation of vomiting center or chemoreceptor trigger zone in CNS
rather than GI toxicity effects
o Receptors for dopamine and serotonin seem to be the most important for triggering 
use drugs to target these
o Reversible
Hair follicle toxicity
o Partial or complete alopecia
o Psychologically distressing
o Reversible, not a health concern


Specific
 Nervous system toxicity
o Vincristine and vinblastine
o Paresthesias of hands and feet, loss of deep tendon reflexes, weakness
 Cardiac toxicity
o Doxorubicin and daunorubicin
o Acute or chronic, potentially irreversible, cardiotoxicity
 Pulmonary toxicity
o Bleomycin
 Urinary tract toxicity
o Cisplatin
o Assoc with renal tubular damage
o Aggressive hydration and diuresis can reduce toxic effect
 Hypersensitive rxns
o Bacterially-derived L-asparaginase (foreign protein)
 Carcinogenic properties
o Alkylating agents (anthracyclines, procarbazine) are mutagenic and carcinogenic 
increased, delayed incidence of 2nd malignancies
Resistance of tumor cells
o 2nd major limitation
o Some tumors inherently resistant to most anticancer drugs and other develop resistance after prolonged low dose
treatment
o Types of resistance
 Decreased conc of drug in cells – decreased uptake, increased efflux
 Decreased level of active drug in cells – increase in cellular enzymes that inactivate drug, decrease in
cellular enzymes required to convert drug to active form
 Altering target – formation of mutated form of drug-targeted enzyme or protein, increased expression of
enzyme that drug is inhibiting
 Repair of damage – increased repair of DNA damage caused by drug
Combination therapy
 Different drugs have different mechanisms of action
 Key advantages of combo therapy
o Provides maximal cell killing within range of toxicity tolerated by patient for each drug
o Provides a broader range of coverage of resistant cell subpopulations in a heterogeneous tumor population
o Prevents or slows the development of new resistant populations
Signal Transduction
 Cascade of molecular events that allow a cell to convert extracellular signals into specific cellular responses
 Changes in gene expression regulate normal cell growth, survival, and differentiation
 Many signal transduction proteins are mutated or overexpressed in human cancers, and consequently, are activated in a
stimulus-indep nature
o Renders cancer cells autonomous of extracellular signal regulation
 Protein kinases
o Proteins utilize ATP to catalyze the transfer of phosphate to serine, threonine, or tyrosine residues in proteins with
protein phosphorylation causing changes in protein function
o Protein tyrosine kinases have been successfully targeted for development of kinases inhibitors as anti-cancer drugs
 HER2 overexpression in breast cancer  trastuzumab monoclonal Ab
 Epidermal growth factor receptor (EGFR) in lung and colon cancer  Iressa/Gefitinib, erlotnib, cetuximab
(erbitux)
 BCR-ABL and CML  Imatinib (Gleevec)
 Tumor angiogenesis (VEGF)  Bevacizumab/Avastin
B.
Monoclonal Antibodies (MAbs)
Cetuximab (Erbitux)
Kinase
Gefitinib (Iressa)
Kinase
Epidermal Growth
Factor Receptor
*Mutations
Small Molecule Tyrosine Kinase Inhibitors (TKIs)
C.
E.
BCR
BCR-Abl
TAFs (e.g. VEGF)
Ph Chromosome
Ch 22
Abl
Blood vessel
Ch 9
der 9
Tumor production of angiogenesis factors recruits blood
vessels into tumor
D.
Abl
Kinase
F.
BCR
BCR-Abl
Bevacizumab
Kinase
VEGF
Normal Endothelial Cell
Tumor Cell