Cancer cells divide rapidly (cell cycle is accelerated)
They are “immortal”
Cell-cell communication is altered
Ability to metastasise
The Goal of Cancer Treatments
Total irradication of cancer cells
Curable cancers include testicular tumors, Wills tumor
Alleviation of symptoms
Avoidance of life-threatening toxicity
Increased survival and improved quality of life
Attempt to eradicate microscopic cancer after surgery
e.g. breast cancer & colorectal cancer
Six Established Rx Modalities
Major approaches to therapy of cancers
Cell Cycle = Growth, Division
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 10 9 cells
The patient is symptomatic at 10 10 -10 11 cells
Dies at 10 12 cells.
Combinations of agents with differing toxicities & mechanisms of action are often employed to overcome the limited cell kill of individual anti cancer agents. Each drug selected should be effective alone
3 advantages of combination therapy:
1. Suppression of drug resistance - less chance of a cell developing resistance to 2 drugs than to 1 drug.
2. Increased cancer cell kill - administration of drugs with different mechanisms of action.
3. Reduced injury to normal cells - by using a combination of drugs that do not have overlapping toxicities, we can achieve a greater anticancer effect than we could by using any one agent alone.
Resistance to Cytotoxic Drugs
Increased expression of
MDR-1 gene for a cell
MDR-1 gene is involved
with drug efflux
Drugs that reverse MDR :
MDR increases resistance
to natural drug products
including the anthracyclines, vinca alkaloids, and epipodophyllotoxins
Modes of Resistance to Anticancer Drugs Mechanism Drugs or Drug Groups Change in sensitivity (or ↑ level) or ↓ binding affinity of target enzymes or receptors Etoposide, methotrexate, vinca alkaloids , estrogen & androgen receptors Decreased drug accumulation via ↑ expression of glycoprotein transporters, or ↓ permeability Methotrexate, alkylating agents, dactinomycin Formation of drug-inactivating enzymes Purine & pyrimidine antimetabolites Production of reactive chemicals that “trap” the anticancer drug Alkylators, bleomycin, cisplatin. doxorubicin Increased nucleic acid repair mechanisms Alkylating agents, cisplatin Reduced activation of pro-drugs Purine & pyrimidine antimetabolites
General problems with anticancer drugs
Most of them are antiproliferative, i.e. they damage DNA and so initiate apoptosis.
They also affect rapidly dividing normal cells.
This leads to toxicity which are usually severe.
To greater or lesser extent the following toxicities are exhibits by all anticancer drugs.