1. ANTINEOPLASTICS I: GENERAL CONCEPTS

2. ESSENTIAL MATERIAL FROM OTHER LECTURES
REFERENCES Katzung Basic and Clinical Pharmacology (10th ed.) Chapter 55, pg
ESSENTIAL MATERIAL FROM 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

3. CRITICAL FACTS

4. 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.

6. REVIEW OF THE PROBLEM

7. Distinguishing Characteristics of Cancer

8. “Non” Evidenced Based Medicine
CANCER TREATMENT cure = 5 year survival
LOCAL TREATMENTS Radiation Surgery 33
CHEMOTHERAPY 17
TOTAL (1999) 5 year survival in 2003 was 62% 50

9. 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.

10. Processes Targeted by Antineoplastic Drugs

11. Cells Affected by Antineoplastic Drugs that Target Rapid Cell Growth

12. 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).
Cell Cycle Specificity G1 M G2 S

13. CELL CYCLE NON-SPECIFIC DRUGS
CYCLE SPECIFIC DRUGS
CELL CYCLE NON-SPECIFIC DRUGS

14. 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).

15. Cell Kill Hypothesis
Critical Points

16. Cell Kil Hypothesis

17. Factors Affecting Outcome
CANCER
PATIENT

18. 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.

19. Drug Resistance
Mechanisms:

20. Drug Resistance
Contributing causes:

21. Multidrug Resistance (decreased accumulation)

22. MECHANISMS OF ACTION

23. PREVENT DNA SYNTHESIS DISRUPT DNA and/or PREVENT RNA SYNTHESIS
Prevent nucleotide synthesis (antimetabolites)
Inhibit DNA synthesizing enzymes
DISRUPT DNA and/or PREVENT RNA SYNTHESIS
Crosslinking agents
Intercalating agents
Drugs that cause DNA strand breaks
INTERRUPT MITOSIS
Inhibit spindle formation
Enhance spindle formation
IMMUNE SYSTEM MODIFIERS
Immunosuppressants
Cytokines and Antibodies
DRUGS THAT ALTER PROTEIN FUNCTION
Signal transduction inhibitors
Miscellaneous
ANGIOGENESIS INHIBITORS
DIFFERENTIATING AGENTS
DRUGS THAT INTERFERE WITH HORMONE FUNCTION
SUPPORTING AGENTS