ANTINEOPLASTICS I:GENERAL CONCEPTS

REFERENCESKatzung Basic and Clinical Pharmacology (10th ed.)

Chapter 55, pg. 878-882

ESSENTIAL MATERIALFROM OTHER LECTURES

• Cell division & cell cycle and apoptosis, especially cell cycle and p53- Dr. Holy, Principles – there is a link to this material on my website

• DNA structure and replication- Dr. Perkins, Principles.

• Regulation of gene expression and Multifactorial nature of cancer– Dr. Cormier, Principles

• Principles of Pharmacology– Dr. Knych, Principles

• Cell injury and cell death and Neoplasia- Dr. Ward, Histopathology

CRITICAL FACTS

1. The GOAL is to eradicate the cancer cells without aff ecting normal tissues

(the concept of DI FFERENTI AL SENSI TI VI TY). The REALI TY is that all

cytotoxic drugs aff ect normal tissues as well as malignancies aim for a

favourable therapeutic index.

2. Cancer drugs can be divided into two general classes: CELL CYCLE SPECI FI C

DRUGS (CCS; esp. plant alkaloids and antimetabolites), and CELL CYCLE

NON- SPECI FI C DRUGS (CCNS; esp. alkylating agents and some natural

products). Antineoplastic agents can also be organized according to their

chemical class, mechanism of action, therapeutic use or their toxicities.

3. The CELL KI LL HYPOTHESI S proposes that actions of CCS drugs follow

fi rst order kinetics: a given dose kills a constant PROPORTI ON of a tumor

cell population (rather than a constant NUMBER of cells).

4. Resistance to cancer chemotherapeutic drugs is a major limitation to

treatment. PRI MARY RESI STANCE occurs when some inherent

characteristic of the cancer cells prevents the drugs f rom working;

ACQUI RED RESI STANCE occurs when cancer cells become resistant during

treatment. MULTIDRUG RESI STANCE is particularly problematic; this

occurs when tumour cells become cross-resistant to a wide range of

chemically dissimilar agents af ter exposure to a SI NGLE (typically natural

product) drug.

5. Based on mechanism of action, there are 8 major categories of antineoplistic

drugs: 1) drugs that prevent DNA synthesis, 2) drugs that disrupt DNA

and/ or RNA synthesis, 3) antimitotics, 4) immune system modifi ers,

5) drugs that interf ere with protein function, 6) angiogenesis inhibitors,

7) diff erentiating agents, and 8) drugs that interfere with hormone

f unction. Supporting agents must also be considered when discussing

antineoplastics.

LEARNING OBJECTIVES

• List the potential targets and actual mechanisms of action of antineoplastic drugs. Be able to rank these with respect to specificity and be able to predict side effects based on the types of cells that are targeted by these agents.

• Compare and contrast the properties of cell cycle specific (CCS) and cell cycle non-specific drugs.

• Describe the cell kill hypothesis and its implications for treatment. Generate a mathematical appreciation for scheduling and dosing regimens used to eliminate cancer cells.

• List the factors that influence the success of chemotherapy and relate those factors to drug administration and choice of antineoplastic agent.

• List the generic mechanisms for antineoplastic drug resistance and the factors that contribute to the development of resistance. Be able to give examples of primary, acquired and multidrug resistance.

• Outline the strategies used in cancer chemotherapy, and be able to give an example of each.

REVIEW OF THE PROBLEM

Distinguishing Characteristics of Cancer

“Non” Evidenced Based Medicine

CANCER TREATMENTcure = 5 year survival

LOCALTREATMENTS

RadiationSurgery

33

CHEMOTHERAPY 17

TOTAL (1999)5 year survival in 2003 was 62%

50

GENERAL CONCEPTS

The GOAL is to eradicate the cancer cells without affecting normal tissues (the goal of DIFFERENTIAL SENSITIVITY). The REALITY is that all cytotoxic drugs affect normal tissues as well as malignancies aim for a favourable therapeutic index.

Processes Targeted by Antineoplastic Drugs

Cells Affected by Antineoplastic Drugs that Target Rapid Cell Growth

Cell Cycle Specificity

Cancer drugs can be divided into two general classes: CELL CYCLE SPECIFIC DRUGS (CCS; esp. plant alkaloids and antimetabolites), and CELL CYCLE NON-SPECIFIC DRUGS (CCNS; esp. alkylating agents and some natural products).

G1

MG2

S

CYCLE SPECIFIC DRUGSCELL CYCLE

NON-SPECIFIC DRUGS

Cell Kill Hypothesis

The CELL KILL HYPOTHESIS proposes that actions of CCS drugs follow first order kinetics: a given dose kills a constant PROPORTION of a tumor cell population (rather than a constant NUMBER of cells).

Cell Kill Hypothesis

Critical Points

Cell Kil Hypothesis

Factors Affecting Outcome

CANCER PATIENT

Drug Resistance

Resistance to cancer chemotherapeutic drugs is a major limitation to treatment. PRIMARY RESISTANCE occurs when some inherent characteristic of the cancer cells prevents the drugs from working; ACQUIRED RESISTANCE occurs when cancer cells become resistant during treatment. MULTIDRUG RESISTANCE is particularly problematic; this occurs when tumour cells become cross-resistant to a wide range of chemically dissimilar agents after exposure to a SINGLE (typically natural product) drug.

Drug Resistance

Mechanisms:

Drug Resistance

Contributing causes:

Multidrug Resistance(decreased accumulation)

MECHANISMS OF ACTION

1.PREVENT DNA SYNTHESISa.Prevent nucleotide synthesis (antimetabolites)b.Inhibit DNA synthesizing enzymes

2.DISRUPT DNA and/or PREVENT RNA SYNTHESISa.Crosslinking agentsb.Intercalating agentsc.Drugs that cause DNA strand breaks

3.INTERRUPT MITOSISa.Inhibit spindle formationb.Enhance spindle formation

a.IMMUNE SYSTEM MODIFIERS1.Immunosuppressants2.Cytokines and Antibodies

b.DRUGS THAT ALTER PROTEIN FUNCTIONa.Signal transduction inhibitorsb.Miscellaneous

c.ANGIOGENESIS INHIBITORSd.DIFFERENTIATING AGENTSe.DRUGS THAT INTERFERE WITH HORMONE FUNCTIONf.SUPPORTING AGENTS