Cancer Chemotherapy TopicsCancer Chemotherapy Topics

1.1. Basic principles: cell cycle, tumor growth Basic principles: cell cycle, tumor growth kinetics, log kill, recruitment, drug targetskinetics, log kill, recruitment, drug targets

2.2. Mechanisms of drug actionMechanisms of drug action

3.3. Drug resistance mechanismsDrug resistance mechanisms

4.4. Toxicity and new approachesToxicity and new approaches

Cellular Cellular Pathways Pathways to to MalignancMalignancyy

Tumor Suppressor GenesTumor Suppressor Genes

Cancer Molecular PathwaysCancer Molecular Pathways

History of Cancer ChemotherapyHistory of Cancer Chemotherapy

Cancer Chemotherapy: Cancer Chemotherapy: Targets for selective toxicityTargets for selective toxicity

target rapidly dividing cells?target rapidly dividing cells? cancer cells are not the only replicating cellscancer cells are not the only replicating cells

• e.g. intestinal epithelia, bone marrow, mucosal, hair follicle e.g. intestinal epithelia, bone marrow, mucosal, hair follicle cells are all rapidly dividing as wellcells are all rapidly dividing as well

not all cells in a tumor are replicatingnot all cells in a tumor are replicating

Cancer Chemotherapy: Cancer Chemotherapy: Targets for selective toxicityTargets for selective toxicity

target rapidly dividing cells?target rapidly dividing cells? cancer cells are not the only replicating cellscancer cells are not the only replicating cells

• e.g. intestinal epithelia, bone marrow, mucosal, hair follicle cells are all e.g. intestinal epithelia, bone marrow, mucosal, hair follicle cells are all rapidly dividing as wellrapidly dividing as well

not all cells in a tumor are replicatingnot all cells in a tumor are replicating

altered metabolic enzymes (e.g. L-asparaginase to kill cells that can not altered metabolic enzymes (e.g. L-asparaginase to kill cells that can not synthesize asparagine)synthesize asparagine)

cell surface receptors (e.g. trastuzumab (Herceptin) blocks HER2 cell surface receptors (e.g. trastuzumab (Herceptin) blocks HER2 (ErbB) in breast cancer)(ErbB) in breast cancer)

specific hormonal requirements (e.g. steroid receptor antagonists for specific hormonal requirements (e.g. steroid receptor antagonists for breast CA, prostate CA)breast CA, prostate CA)

altered intracellular signaling (e.g. imatinib (Gleevec) targets the Abl altered intracellular signaling (e.g. imatinib (Gleevec) targets the Abl kinase which is turned on in chronic myelocytic leukemia)kinase which is turned on in chronic myelocytic leukemia)

Remissions and complete cures are Remissions and complete cures are obtained with specific cancersobtained with specific cancers

Hodgkin’s lymphomaHodgkin’s lymphoma choriocarcinomachoriocarcinoma acute leukemias in childrenacute leukemias in children Wilm’s tumor (kidney)Wilm’s tumor (kidney) testicular cancertesticular cancer breast, prostate CAbreast, prostate CA

The cell cycleThe cell cycleG1G1: growth, protein : growth, protein synthesis, RNA synthesis, RNA synthesissynthesis

S: S: DNA synthesis, DNA synthesis, replication, RNA & replication, RNA & protein synthesisprotein synthesis

G2:G2: DNA repair, DNA repair, chromosome chromosome condensationcondensation

M:M: mitosis, nuclear mitosis, nuclear divisiondivision

Restriction point: cells traverse R by Restriction point: cells traverse R by expression and activation of cyclin/CDK expression and activation of cyclin/CDK

complexes and then are committed to continue complexes and then are committed to continue through S phase.through S phase.

Cell Cycle SpecificCell Cycle Specific fluorouracilfluorouracil mercaptopurinemercaptopurine methotrexatemethotrexate

L-asparaginaseL-asparaginase

paclitaxelpaclitaxel vincristine/vinblastinevincristine/vinblastine

Cycle non-specificCycle non-specific alkylating agents:alkylating agents:

• cyclophosphamide, cyclophosphamide, mechlorethamine, mechlorethamine, nitrosoureasnitrosoureas

actinomycin Dactinomycin D daunorubicin, doxorubicindaunorubicin, doxorubicin etoposide, irinotecanetoposide, irinotecan

cisplatincisplatin bleomycinbleomycin

Cell Cycle Specificity of Cell Cycle Specificity of Selected DrugsSelected Drugs

Tumor growth kineticsTumor growth kinetics

Log Kill hypothesisLog Kill hypothesis

Dr. Howard SkipperDr. Howard Skipper 1960s1960s postulated that cell death follows 1st order postulated that cell death follows 1st order

kinetics with anti cancer drugskinetics with anti cancer drugs experiment: treat mouse leukemia with experiment: treat mouse leukemia with

cytosine arabinosecytosine arabinose• 24 hr of ara-C--mice died24 hr of ara-C--mice died• 3 treatment every 4 days--mice lived3 treatment every 4 days--mice lived

developed concept of Log Kill developed concept of Log Kill

Easy Exam QuestionEasy Exam Question

As part of your research project you are experimenting with As part of your research project you are experimenting with the treatment of mice injected with 10the treatment of mice injected with 101212 leukemia cells. leukemia cells.You are using a combination of mechlorethamine andYou are using a combination of mechlorethamine andvincristine with a log kill of 4. The leukemia grows atvincristine with a log kill of 4. The leukemia grows ata rate of 1 log per week. If you start treatment immediatelya rate of 1 log per week. If you start treatment immediatelyand give a treatment every 2 weeks, what is the minimumand give a treatment every 2 weeks, what is the minimumnumber of treatments required to theoretically cure yournumber of treatments required to theoretically cure yourmouse patients?mouse patients?

A)A) 33B)B) 44C)C) 55D)D) 66E)E) 77

Harder Exam questionHarder Exam question

The initial tumor burden is 10The initial tumor burden is 101010 cells and the drug combination cells and the drug combinationused is known to give a log kill of 3. Assuming a 1 log re-growthused is known to give a log kill of 3. Assuming a 1 log re-growthper week between treatments and that all the cells are sensitive, per week between treatments and that all the cells are sensitive, which of the following treatment schedules would be expectedwhich of the following treatment schedules would be expectedto give a complete cure (ignoring the fact that cancers don’tto give a complete cure (ignoring the fact that cancers don’talways behave predictably)?always behave predictably)?

A. A. 3 treatments at one week intervals3 treatments at one week intervalsB. B. 8 treatments at two week intervals8 treatments at two week intervalsC. C. 50 treatments at three week intervals50 treatments at three week intervalsD. D. 5 treatments at one week intervals5 treatments at one week intervalsE. E. none of the abovenone of the above

RecruitmentRecruitment

non-dividing cellsnon-dividing cells(insensitive to (insensitive to many drugs)many drugs)

rapidly dividing rapidly dividing cellscells

(sensitive to (sensitive to drugs)drugs)

•increase nutrient supplyincrease nutrient supply•increase perfusionincrease perfusion•reduce crowding:reduce crowding:

surgerysurgeryradiationradiationchemo with cycle non-specific drugschemo with cycle non-specific drugs

(e.g. alkylating agents)(e.g. alkylating agents)

Hypoxia in tumor induces expression of Hypoxia in tumor induces expression of angiogenic genesangiogenic genes

bevacizumab bevacizumab (Avastin) (Avastin) antibody toantibody toVEGFVEGF

Drug Targets in Cancer ChemotherapyDrug Targets in Cancer Chemotherapy1. DNA1. DNA

a) bondagea) bondage--alkylating agents --alkylating agents (mechlorethamine, cyclophosphamide), (mechlorethamine, cyclophosphamide), cisplatincisplatinb) vaporizationb) vaporization--bleomycin--bleomycin

c) confusionc) confusion--actinomycin D, doxorubicin, etoposide, --actinomycin D, doxorubicin, etoposide, irinotecanirinotecan

d) starvationd) starvation--methotrexate, 6-thioguanine, --methotrexate, 6-thioguanine, 5-fluorouracil, cytosine arabinoside,hydroxyurea5-fluorouracil, cytosine arabinoside,hydroxyurea

e) regulatione) regulation--tamoxifen, aromatase inhibitors--tamoxifen, aromatase inhibitors2. Protein synthesis: 2. Protein synthesis: L-asparaginase L-asparaginase

3. Mitotic Apparatus: 3. Mitotic Apparatus: vincristine, vinblastine, paclitaxel vincristine, vinblastine, paclitaxel

4. Specific antigens:4. Specific antigens: therapeutic antibodies (e.g. therapeutic antibodies (e.g. Herceptin, Herceptin, Avastin)Avastin)

5. Protein kinase inhibitors:5. Protein kinase inhibitors: Gleevec (imatinib) Gleevec (imatinib) inhibits inhibits BCR-ABL which causes CMLBCR-ABL which causes CML(chronic (chronic myeloid leukemia)myeloid leukemia)