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 Non-Specific 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 hypothesis:

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