Etiology:
Environmental carcinogens – azo dyes, afltoxins, asbestos, benzene
Viruses: herpes , papilloma , HTLV
Amplification of oncogenes (proto-onco), deletion of tumor suppressor genes (p53)
Shift in the control mechanisms that govern
cell proliferation
and
differentiation
Genetics vs. Environment
Theory: “Genetics loads the gun; the environment pulls the trigger
Normal cells…
Differentiate, grow, mature, divide
Regulated, balanced; cell birth=cell death
Regulation: intracell signaling
Hyperplasia: new cells prod’d w/ growth stimulus via hormones, endogenous signals
Ex: hyperplasia of endometrial tissue during menstrual cycle is normal and necessary
BUT if intense, prolonged demand …May cell structural, functional abnormalities
Metaplasia: replacement of one cell type by another
Thicker cell layer better accommodates irritation
Ex: bronchial epithelium chronically irritated ciliated columnar epithelial cells replaced by sev layers cuboidal epithelium
Note: Replacement cells normal, just different
Reversible
Dysplasia: replacement cells disordered in size, shape
Incr’d mitosis rate
Somewhat reversible, often precancerous
Neoplasia: abnormal growth/invasion of cells
“New growth”
Neoplasm = tumor
Irreversible
Cells replicate, grow w/out control
The growth cycle of a cell is its major determinant of responsiveness to chemotherapy. A measure of cell growth is the cell cycle. The cell cycle consists of four major phases: G1, S, G2 & M
1. G1 phase - cell prepares to make DNA.
2. S phase - DNA synthesis takes place.
3. G2 phase - synthesis of components needed for mitosis.
4. M phase - mitosis (cell division) occurs.
Importance of cell cycle kinetics
Cell Cycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction
Most effective in hematologic and solid tumors with high growth fraction
CCNS drugs bind to DNA and damage it. Are useful in low growth fraction solid tumors as well as high growth fraction tumors.
CCS kill only cycling cells, whereas CCNS drugs kill cell that are cycling or in G0 (quiescent)
Cycling cells are more sensitive
Effective in low growth fraction as well as high growth fraction solid tumors
Importance of cell cycle kinetics
Cell Cycle Specific (CCS) drugs are useful in tumors with large proportions of proliferating cells or cells in the growth fraction
Most effective in hematologic and solid tumors with high growth fraction
CCNS drugs bind to DNA and damage it. Are useful in low growth fraction solid tumors as well as high growth fraction tumors.
CCS kill only cycling cells, whereas CCNS drugs kill cell that are cycling or in G0 (quiescent)
Cycling cells are more sensitive
Effective in low growth fraction as well as high growth fraction solid tumors
Nitrosureas ;Carmustine and lomustine
Highly lipid soluble drugs hence reach high concentration in the brain and CSF.
Mainly used in brain tumors and Hodgkin’s disease
Intracellular formation of polyglutamate metabolites is critically important for the therapeutic action of MTX. MTX polyglutamates are selectively retained within cancer cells, and they display increased inhibitory effects on enzymes involved in de novo purine nucleotide and thymidylate biosynthesis, making them important determinants of MTX's cytotoxic action.