Principle of Chemotherapy (II)

Chemotherapy

the use of cytotoxic chemical agents to destroy cancer cells ​

Targeted therapy

drugs used to inhibit specific molecular targets

Biologic therapy (immunotherapy)

drugs used to boost the immune system to function better​

What is the goal of chemotherapy drugs?

to kill cancer cells, no harm tonormal cells​

Using the differences between cancer and normal cells

most cancer cells grow at a rate faster than normal cells (but not always) ​

Whats cells are most affected and least disturbed in chemotherapy?

Fast-growing cells affected the most and slow-growing cells least disturbed

The growth of tumor

cell dividing through a cell cycle​

How do chemotherapy drugs work?

• Most chemotherapy drugs interfere with the cell cycle​

• Related to side effect profiles: damaging hair follicles, bone marrow, skin, and the cells in GI tract (these are also fastest growing cells) ​

Cell cycle

• A proliferating (dividing) cell progresses throughcell cycle (5 phases):​

• M – mitosis​ (1h duration)

• G0 – dormant (not dividing)​

• G1 - first gap phase (postmitotic phase)​ (highly variable)

• S - DNA synthesis​ (8-20h duration)

• G2 - second gap phase (premitotic phase)​ (3h duration)

• Cell cycle is regulated by many factors such ascytokines, hormones, growth factors

Growth fraction​

• A proliferating cancer cell has three possible fates: ​

(1) the daughter cell can become quiescent by entering G0​

(2) can enter G1 and proliferate, or ​

(3) the cell can die​

• The ratio of the number of cells that areproliferating to the total number of cells in the tumor is called growth fraction. ​

• An average tumor growth fraction for solid tumor is ~20%; leukemia ~100%​

• Most chemotherapy drugs target the dividingcells (i.e., the cells that are in the cell cycle)​

• Most normal cells are in the G0 phase; cancercells can be in G0 also (cells in G0 phase arenot sensitive to chemotherapy)​

• However, some cells in normal tissues havehigh growth fractions (bone marrow and GI mucosa), resulting in toxicities

Tumor properties affecting chemotherapy​

• Tumor Size​

• Tumor Growth Rate (growth fraction)​

• Tumor Cell-Cycle Phase​

• More effective in cancers with high growth factions, such as leukemias often respond more than large bulky tumors​

• Cytotoxic drugs are most effective in rapidly growing tumors and when tumors are small, because growth fraction is high

cell cycle phase-specific (CCS)agents. ​

Agents with major activity in a particular phase of thecell cycles

Cell cycle phase-nonspecific (CCNS) agents

active in multiple phases. e.g. alkylating agents.​

Knowledge of cell cycle specificity has been applied to the scheduling of chemotherapy administration

different classes of drugs, CCS and CCNS, can be used incombination.​

Limitations - chemotherapy​

1. Dose-related systemic toxicity: Due tonon-selective toxic effects to both tumorand normal cells​

2. Drug resistance: multiple mechanisms​

3. Treatment-induced tumors

Combination Drug Therapy

Combination-drug therapy is more successful than single-drug treatment in most of cancers - to achieve long-term remission, prevent drug resistance and reduce ADRs​

Principles for combination

to combine agents with different toxicities, different molecular targets and mechanisms, different cell cycle phase specificity