chemotherapy is part of pharmacology that talks about the antibiotics that used to kill or inhibit the growth of bacteria or microbs it also talks about how to treat the body by using the chemical substances .

1. A, B, Cs of
CHEMOTHERAPY
Pediatric Resident
Education Series

2. THE CELL CYCLE
G1
S
G2
M
Go
CELL LOSS
G1 PROTEIN SYNTHESIS
S DNA SYNTHESIS
G2 PREMITOSIS
M MITOSIS
Go RESTING
CELLS THAT DIE OR MATURE
DO NOT CONTRIBUTE (ARE
“LOST”) TO TUMOR GROWTH

3. TUMOR GROWTH
A. ALL CELLS IN CYCLE
DT = CT
B. A FRACTION IN CYCLE
DT = CT
GF
C. A FRACTION IN CYCLE
WITH CELL LOSS
DT = CT
GF x CL
DT DOUBLING TIME
CT AVERAGE CYCLE TIME
GF GROWTH FRACTION
CL CELL LOSS
WHEN CL IS > 0.5 GROWTH
OF A TUMOR CEASES

4. LUNG METASTASIS GROWTH
LOG #
TUMOR
CELLS
TIME
TMD
TMO
TPD
TMO TIME METASTASIS ORIGIN
TMD TIME METASTASIS DIAGNOSED
TPD TIME PRIMARY DIAGNOSED

5. TUMOR GROWTH CONTROLS
 Large tumors grow slowly because of
limitations in oxygen/nutrient supply and
waste elimination
solution: tumor angiogenesis
 Mid-sized tumors grow logarithmically
 Small tumors grow slowly because of
residual normal growth control mechanisms
solution: additional mutations increase
growth independence

6. MICROMETASTASES
AT THE TIME OF PRIMARY TUMOR DIAGNOSIS
MICROSCOPIC METASTATIC TUMOR DEPOSITS ARE PRESENT
IN MOST PATIENTS
WILMS TUMOR: WITHOUT CHEMOTHERAPY, 80 % OF NEWLY
DIAGNOSED PATIENTS WITH NORMAL CXR DEVELOP LUNG
METASTASES DESPITE IMMEDIATE NEPHRECTOMY
OSTEOSARCOMA: WITHOUT CHEMOTHERAPY, 90 % OF NEWLY
DIAGNOSED PATIENTS WITH NORMAL CXR DEVELOP LUNG
METASTASES DESPITE IMMEDIATE AMPUTATION
ALL: WITHOUT CNS “PROPHYLAXIS”, 70 % OF NEWLY DIAGNOSED
PATIENTS WITH A NORMAL CSF DEVELOP CNS LEUKEMIA

7. CHEMOTHERAPY KINETICS
Tumor cell kill depends upon drug dose. For many
agents the dose response curve is steep.
LOG KILL HYPOTHESIS: in log phase growth,
the fraction of cells killed is dependent on drug
dose and is independent of tumor cell numbers
Example: 2 log cell kill 106 104
104 102
4 log cell kill 106 102
104 100

8. CHEMOTHERAPY KINETICS
FREQUENCY
RESIDUAL TUMOR CELLS
0 1 10 100 1000
4 LOG CELL KILL
STARTING CELL #
106
104
CURE IS MORE LIKELY WHEN THERE IS A
LOWER TUMOR CELL BURDEN AT THE
INITIATION OF THERAPY

9. CHEMOTHERAPY KINETICS
MUTATIONS AT SPECIFIC LOCUS OCCUR AT A
FREQUENCY OF 1/1,000,000 CELL DIVISIONS
%
SENSITIVE
CELLS
100
0
TIME or CELL DIVISIONS
STARTING CELL #
106
104

10. CHEOTHERAPY KINETICS
i.e., TREATMENT IS USUALLY MOST EFFECTIVE WHEN:
DOSES ARE HIGH [INTENSIVE THERAPY]
TUMOR BURDEN IS LOW [MINIMAL DISEASE]
THIS STRATEGY WORKS BY SEVERAL MECHANISMS:
ELIMINATION OF SENSITIVE CELLS
PREVENTING DEVELOPMENT OF RESISTANT CELLS
TREATMENT OF RESISTANT CELLS

11. CHEMOTHERAPY KINETICS
LOG
TUMOR
CELLS
1012
TIME
0
SENSITIVE CELLS
RESISTANT CELLS
TOTAL CELLS
1010 [REMISSION]
WHAT STRATEGY IS BEST TO PREVENT RELAPSE?

12. CHEMOTHERAPY STRATEGY
Given a series of drugs (or drug combinations),
what is the optimal strategy:
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13. GOLDIE-COLDMAN HYPOTHESIS
Optimal tumor treatment would use a large series of
non-repeating drugs or drug combinations
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This hypothesis is based on several assumptions:
Log growth of tumor cells X
Equal effectiveness of drugs X
Different mechanisms of action of drugs X
Different toxicities of drugs X
ASSUMPTIONS MARKED X ARE NOT MET IN MOST
CLINICAL SETTINGS

14. DRUG SCHEDULE
Many patient, disease and treatment factors affect
the efficacy and toxicities of drugs
DOSE
ROUTE
FREQUENCY
TIMING
CONCOMMITANT MEDICATIONS
METABOLIZING ENZYMES
HEPATIC, RENAL FUNCTION
NUTRITION
SENSITIVITY

15. DRUG SYNERGY, ANTAGONISM, and
ADDITIVE EFFECTS
 Drug effects are additive when their use in
combination gives results equivalent to their
sequential independent use.
 Lesser effects suggest antagonism.
 Greater effects suggest synergism.

16. DRUG SYNERGY, ANTAGONISM, and
ADDITIVE EFFECTS
 Drug A 60 % response
 Drug B 30 % response
 Drug A + B
60 respond to A
12 respond to B [30 % of 40
non-responders to A]
72 % = additive response rate
A lower response rate would suggest antagonism; a
higher response rate would suggest synergism

17. SYNERGY, ANTAGONISM, and ADDITIVE
EFFECTS: OSTEOSARCOMA
 No chemotherapy: 10 % EFS
 High dose methotrexate: 50% EFS
 Doxorubicin: 50% EFS
 Methotrexate + doxorubicin: 50 % EFS
EXPLANATION: because of overlapping
toxicities, both drugs had to be scheduled
at longer intervals than when used alone

18. DRUG SYNERGY, ANTAGONISM, and
ADDITIVE EFFECTS: ALL
 Methotrexate [Mtx] followed by asparaginase
is synergistic
 Asparaginase [Asn] followed by methotrexate
is antagonistic
EXPLANATION: Mtx kills in S phase; this
recruits cells into G1 where they are most
susceptible to Asn. With initial Asn, cells are
killed in G1 leaving few to enter S where Mtx
is most effective.

19. GENERAL APPROACHES TO
CHEMOTHERAPY PROTOCOL DESIGN
 Intensify the use of chemotherapeutic agents
known to be effective
 Modify therapy based on disease response to initial
treatment and/or risk factors for recurrent disease
 Add new agents targeting a specific cell, antigen, or
enzyme/metabolic pathway

23. CREDITS
 Bruce Camitta MD