CANCER CHEMOTHERAPY
Anti Cancer drugs:
1. Historically derived small molecules. Target DNA structure
or segregation of DNA- Conventional chemotherapy
2. Targeted agents:- small molecules or biologicals,
antibodies / cytokines.
2. Targeted agents:
Act against pathways that lead to:
• uncontrolled proliferation,
• loss of cell cycle inhibitors.
• Loss of cell death regulation,
• capacity to replicate chromosomes indefinitely
• invade, metastasize & evade the immune system
3. Hormonal therapies
4. Biological therapies – includes 2 & gene therapies
-
Therapeutic delay
-
Tumor response
-
Anti cancer drug toxicities
Gradation of toxicity:
I. do not require treatment
II. require symptomatic treatment, not life threatening
III. Potentially life threatening if left untreated
IV. actually life threatening
V. death
Response:- induce cancer cell death
-Tumor shrinkage with increase patient survival
-Increase time until disease progresses
-Induce cancer cell differentiation / dormancy,
-Necrosis, apoptosis, Anoikis.
How anti – cancer drugs work:Interaction of drug with target  cascade
Cell -death – “Execution phase”
Proteases, nucleases and endogenous regulators of cell
death pathway are activated.
How targeted agents differ?
Regulate action of particular pathway. NOT
INDISCRIMINATE
eg. P210bcr –abl fusion protein tyrosine Kinase drives
CML
HER – 2 / neul – breast cancer
Resistance
1) Cell not in appropriate phase of cell cycle to allow drug
lethality
2) Decreased uptake
3) Increased efflux
4) Metabolism of the drug
5) Alteration of target
p170 PGP – mdr gene product 121
Combination of drugs:-
1) Efficacy
2) Toxicity
3) Optimum scheduling
4) Mechanism of interaction
5) Avoidance of arbitrary dose changes.
Dosage factors:• Dose escalation
• Reducing interval between treatment cycles
• Sequential scheduling of either single agents or of
combination regimens
Cancer Chemotherapy
• After completion of mitosis, the resulting daughter
cells have two options:
• (1) they can either enter G1 & repeat the cycle or
• (2) they can go into G0 and not participate in the
cell cycle.
• Growth fraction - at any particular time some cells
are going through the cell cycle whereas other cells
are resting.
• The ratio of proliferating cells to cells in G0, is
called the growth fraction.
• A tissue with a large percentage of proliferating
cells & few cells in G0 has a high growth fraction.
• Conversely, a tissue composed of mostly of cells
in G0 has a low growth fraction.
Cell Cycle Specific (CCS) & Cell Cycle NonSpecific Agents (CCNS)
Log kill hypothesis
• According to the log-kill hypothesis,
chemotherapeutic agents kill a constant fraction
of cells (first order kinetics), rather than a
specific number of cells, after each dose
1. Solid cancer tumors - generally have a low
growth fraction thus respond poorly to
chemotherapy & in most cases need to be
removed by surgery
2. Disseminated cancers- generally have a high
growth fraction & generally respond well to
chemotherapy
Log kill
LOG kill hypothesis
• The example shows the
effects of tumor burden,
scheduling, initiation/duration
of treatment on patient
survival.
• The tumor burden in an
untreated patient would
progress along the path
described by the RED LINE
–
• The tumor is detected (using
conventional techniques)
when the tumor burden
reaches 109 cells
• The patient is symptomatic
at 1010-1011 cells
• Dies at 1012 cells.
Primary induction:- chemotherapy Primary treatment
–advanced cancer – no alternative treatment
Curable : Hodgkin's, NHL, AML, Germ cell , choinoca.
Child :- ALL, B’ inkitt’s, Wilma's, embryonal shabdo
myosarcoma.
New adjustment : localized cancer for which
alternative local exist less effective.
- Avil, Bladder, Breast, esoyhagin, laring. NSCLS,
Osteogeric sancoma.
Adjustment: - adjunct to local modalities
eg :. Hormonal agents for g breast