Chemotherapy

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BAG signs

Back 1

Bone marrow, alopecia, gastrointestinal signs

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Chemotherapy

Back 2

non- selective toxicity (normal and neoplastic cells)
target fast dividing cells
induce cytotoxicitiy by damaging DNA or interfering with substrate or enzyme necessary for synthesis and replication of DNA

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somatic and germ line mutation

Back 3

somatic mutation= changes in DNA in course of time= geriatric cancer
germ line mutation- childhood leukemia and other childhood cancer affering germ line during development

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Cell cycle

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G0= quiescent phase where cells are not actively dividing. Most cells are here
G1= protein and enzymes required for DNA synthesis are produced
S= synthesis
G2= protein and enzyme required for protein synthesis, RNA synthesis and mitotic spindle formation
M= mitosis, DNA divide between daughter cells

Front 5

Cell cycle specific drug

Back 5

target S and Mitosis phase, drug not as toxic. Most other drugs affect DNA present in all cells regardless of which cycles they are in

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Checkpoints

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regulates transitions thru each phase
make sure necessary machinery in place prior to getting pass checkpoint
cancer cell DO NOT OBEY checkpoints, so they have growth advantage over normal cell and acquired additional genetic mutation

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5 group Anticancer drug

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1. Alkylating
2. antimetabolites
3. antineoplastic
4. microtubule spindle poisons
5. misc. agents

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Alkylating agents

Back 8

DNA adducts formation by covelent bond
interfere with replication of DNA
cell cycle non specific cytotoxicity
side effects

Front 9

Antimetabolites

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inhibtions of protein or enzyme required for synthesis of DNA (S phase)
cell- cycle specific cytotoxicity

Front 10

Antineoplastic antibiotics

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generate free radicals
inhibition of enzymes necessary to unwind DNA
exert cytotoxic effect on SNA, so cell cycle non- specific cytotoxicity

Front 11

Microtuble spindle poison

Back 11

inhibit mitosis phase, prevent formation or destruciton of mitotic spindle
halting cell cycle in M phase
cell cycle specific agent

Front 12

misc chemo agent

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mechanism similar to alkylating agent, so cell cycle non- specific

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Tumor growth kinetics

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growth limitations dictated by nutrient, oxygen and acidic pH from excessive metabolites
won't keep growing, rapid growth phase and stationary phase, chemo most effective with rapid dividing cell so treat tumor small before they plateau off in stationary phase

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Chemo drug resistance

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1. anatomical compartment
2. tumor microenvironment
3. inherent drug resistance (Goldie- Coleman Hypothesis)
4. Acquired drug resistance (selective pressure evolution)

Front 15

Influence of anatomic compartment

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Sanctuary site with specialized endo cell to impede adequate anticancer drug concentration
prostate, brain, eye
junction may be bypassed with lipophilic agents

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Influence of microenvironment

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factors influence drug delivery:
blood flow, permeability of vessels, interstital fluid pressure within solid tumor
poor flow, decr o2 and nutrients, retarded growth, less susceptible to chemo
solid tumoe, igh interstital pressure, unfavorable pressure gradient for diffusion

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Inherent drug resistnce: goldie coleman hypothesis

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implant systemic chemo early on in dx most effective
in any neopastic popultion, there exist possibility for mutant cell resistant to chemo
for 1cm3 solid tumor, 1000 cells might have resistance, so systemic treamtment of mucroscopic tumor more sucessful than macroscopic tumor

Front 18

Acquired drug resistance: selective pressure

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selection pressure to survive toxic insult (chemo) upregulates pathway equipped to deal with external cellular stresses
result in formation of super hardy and resistant population of cancer cell

Front 19

Dose intensity and combination chemo

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dose intensity= concentration x time
1. apply maximum dose intensity (max tolerated dose at closest possible interval between drugs)
2. combination therapy: population heterogeneity increase likelihood of having cell resistant to one type of chemo