Men die from lung, colorectal, then prostate cancer

Women die from lung, breasts, then colorectal cancer.

Lung cancer and colorectal cancer are still leading cause of cancer death

Cancer Cell Doubling

@ 20, 1mm in mass

@ 27, 0.5 cm

@ 30, 1 cm in mass, palpable.

@ 35, 1 foot in diameter

Tumor growth kinetic pattern

1, Diffused Tumor (acute leukemia)

exponential growth curve

high labelling index (rapid proliferation)

2, Solid Tumor (breast cancer)

exponential growth curve and plateau

lower labelling index

Principles of classical cancer chemo

1, cure=death of every cancer cell

2, do not rely on host mechanism

3, cell-kill follow 1st order kinetics, a constant % of cells are killed.

Chemotherapeutic Drugs

1, Alkylating agent

2, Antimetabolites

3, Modify microbubules

4, DNA damaging agents

Alkylating agents (Nitrogen mustards)

1, Mechlorethamine

electron deficient, alkylate DNA to cause depurination

kills proliferating cells only. eg: leukemia

Very chemically active, IV injectiong to site of tumor only

2, Cyclophosphamide

more stable than mechlorethamine

oral admin for long-term treatment

needs P450 to open the ring and release

1, phosphoamide mustard (active cancer-drug)

2, Acrolein (cause bladder damage due to toxic aldehyde)

3, Cisplatin

organoplatinum compound

binds to 2 molecules of guanine 

form inter/intra strandcrosslinking

may also form crosslink with glutathione

note: tumor cells with lots of glutathion will inactivate the alkylating agents.

Toxicity of Alkylating agents

↓ bone marrow

GI tract damage

Gonads: ↓ germ cells,

reversible/irreversible depending on dose

Resistance to alkylating agents:

1, ↑ inactivation by adding more glutathion

2, ↑ DNA repair

3, ↓ activation.

eg:  P450 on cyclophosphamide

Anti-Metabolites

1a, Methotrexate inhibits mammalian DHFR, starve cell of thymidine. it's metabolized inside the cell.

b, Methotrexate polyglutamate: active metabolite of methotrexate which also block DHFR and synthesis of purine

Resistance for Methotrexate

1, Block transport of methotrexate into cell by

 ↓ effectiveness of folic acid transport system 

2, Block the formation of polyglutamate

3, increase or alter DHFR

4, decrease thymidylate synthase

2, 5-FU

Pyrimidine analog

blocks thymidine sunthesis by forming a complex on thymidylate synthase enzyme

Resistance:

when tumor decrease thymidylate synthase enzyme

3, Cytarabine

with modified sugar arabinose instead of ribose

inhibit DNA chain elongation

active metabolite Ara-CTP

can be inactivated by uracil derivatives.

Resistance by cytidine deanimase