Transcript The Treatment and Prevention of Hereditary Breast cancer with

Special Topics:
Cancer Pharmacology I
Joseph A. De Soto M.D., Ph.D., F.A.I.C.
Why Cancer Pharmacology?
A large number of surgeries are cancer-related.
Treatment of primary neoplasm.
Reconstructive procedures
Staging
Central line placements
Debulking procedures
Neuro-ablative procedures
As a professional your knowledge needs to be broad as others will
come to you for questions.
You future responsibilities may become more than the operating
room such as commanding a hospital.
Introduction
 Cancer is a term that describes several different disorders that have in
common: 1) abnormal cellular growth 2) cellular atypia 3) cellular
immortality 4) the ability to invade 5) the potential to metastasize.
 Cancer develops through a series of stages 1) Initiation where DNA
damage occurs in a cell. 2) Promotion where the mutated cell undergoes
a clonal expansion obtaining further mutations. 3) Progression where
mutations expand exponentially and chromosomal instability occurs
resulting in the duplication or loss of entire chromosomes.
 The main determinant of cancer growth is that more cells are produced
than die at a given time. Frequently, the rate of growth is faster than
normal tissue.
 Most cancers are not detectable until the mass reaches 1 cm3 in volume.
This represents 108-109 cells.
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Epidemiology of Cancer
33% of Americans will develop cancer.
25% of males and 20 % of females will die from cancer
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% of Cancer
1) 32% breast (women)
2) 32% prostate (men)
3) 14.5% lung
4) 12.5 % colon
5) 6.5% urinary
6.5% leukem/lymph
% Death
1) 28% lung
2) 18% breast (women)
3) 13% prostate (men)
4) 10.5 colon
5) 8% leukem/lymph
Cancer Treatment
 The pharmacological treatment of cancer currently consist of three classes of
medications: 1) Chemotherapy – which tend to either interfere with DNA
synthesis , damage DNA or interfere with mitosis. 2) Hormonal treatment –
which blocks the stimulation of growth of tissue by hormones. Thus,
hormonal treatment in a sense are anti-hormonal therapy 3) Biologicals –
this is the newest class of compounds which are antibodies or small
molecules that inhibit receptors on tumor cells or growth factors thus
blocking the stimulation of tumor growth.
Cancer Treatment
 For the most part, most of our therapies eventually fail as
cancer cells rapidly become resistant to treatment. In
addition, we must remember that even if
chemotherapy/hormonal/biological therapy kills 99.0% of
cells in a 1 cm3 tumor (1 billion cells) that leaves 10
million cancer cells still alive. In a large tumor of 10 cm3
100 million cancer cell would be left alive.
Toxicity
 The toxicity of the cancer agents is directly due to their
mechanism of action.
 Most chemotherapeutic agents act most efficiently during the
cell cycle hence normal cells that are frequently in the cell cycle
will also be damaged. The hair, the lining of the G.I. tract, the
bone marrow, skin.
 Hormones, biologicals, chemo drugs may inhibit metabolism
and energy usage and thus organs or systems with high energy
needs may be damaged: Heart, kidneys, nervous system.
Cell Cycle
Anti-Metabolites
Alkylating Agents,
Alkylating Type
Agents
Hormonal
Agents
S DNA
Synthesis
G0
Topoisomerase
Inhibitors
G1 pre-DNA
synthesis
AntiMitotics
M mitosis
Often prolonged
in cancer
G2 PreMitosis
Anti-Metabolites
 Agents: Methotrexate, permetrexed, 5-fluorouracil, capecitabine,
cytosine-arabinoside (ARA-C), gemcitabine, 6-mercaptopurine.
 Mechanism of Action: Anti-metabolites interfere with the synthesis of
DNA by mimicking nucleotides or nucleosides. These drugs are most
active in the S phase of the cell cycle.
Methotrexate and permetrexed inhibit dihydrofolate reductase and thus
inhibit purine synthesis.
5-Flourouracil and capecitabine inhibit thymidylate synthase and thus
inhibit thymidine production.
Ara-C mimics cytosine is incorporated into the DNA and inhibits DNA
polymerase. Gemcitabine acts in a similar fashion to ARA-C.
6-Mercaptopurine inhibits glycolysis and purine synthesis
Anti-Metabolites
 Toxicity:
Methotrexate, permetrexed – Myelosuppression and
mucocytosis. Occasional alopecia and interference with
gametogenesis.
5-Fluorouracil, capecitabine- fulminant diarrhea,
mucositosis.
ARA-C, gemcitabine – severe leukopenia, seizures when
given intra-thecally.
6-Mercaptopurine – moderate bone marrow suppression
Alkylating Agents
 Agents: Cyclophosphamide, mitomycin, dacarbazine, nitrosoureas,
thiotepa, chlorambucil.
 Mechanism of Action: These agents cause inter-strand and intra-strand
cross linking of DNA. Alkylating agents are active when a cell is not in
the cell cycle and thus are useful for slow growing cancers. However, they
do work best when a cell is cycling.
 Toxicity: Acute myelosuppression is the most common toxicity of these
agents with a nadir of peripheral blood counts occurring 6-10 days after
the last dose and recovery occurring at 14-21 days. Gastrointestinal
damage is the next most common toxicity resulting in diarrhea and
sometimes loss of blood. These agents are well know for causing alopecia
Hypocalcemia, hypokalemia, hypomagnesemia may also occur.
 Note: Cyclophosphamide tends to spare platelets.
Platinum Type Alkylating Agents
 Agents: Cisplatin, oxaliplatin, carboplatin
 Mechanism of Action: Intra-strand and inter-strand cross
linking. Especially A-G cross linkage.
 Toxicity: Ototoxicity, nephrotoxicity, marked nausea and
vomiting, hypocalcemia, hypokalemia, hypomagnesemia.
 Cisplatin- ototoxicty and nephrotoxicity,
 Carboplatin- myelosuppression, mild neuro and nephrotoxicity.
Most mild of the platinum alkylating agents.
 Oxaliplatin- peripheral neuropathy.
Anti-Mitotic Agents
Agents: Paclitaxel, docetaxel, vincristine, vinblastine.
Mechanism of Action: These agents either stabilize or destabilize
microtubules interfering with mitosis and the intracellular
transport of organelles. Paclitaxel and docetaxel stabilize
microtubules inhibiting depolymerization. Vincristine and
vinblastine de-stabilize microtubules inhibiting polymerization.
Toxicity:
Paclitaxel – Edema, neutropenia at 8-11 days after last dose.
Stock and glove neuropathy, allergic reactions, anaphylaxis.
Docetaxel – Edema, peripheral neuropathy, bone marrow
suppression, severe fatigue, allergic reactions, anaphylaxis.
Vinblastine- Leukopenia at 7 days after last dose, diarrhea.
Vincristine – Progressive neurological toxicity, constipation,
bowel obstruction.
Topoisomerase Inhibitors
 Agent: Doxorubicn, daunorubicin, etoposide, mitoxantrone,
irinotecan.
 Mechanism of action: These agents inhibit topoisomerase and
hence the unwinding of DNA during DNA replication. They
may also cause strand breakage.
 Toxicity: Doxorubicin may cause CHF in 30% of patients
occurring months or years later. In 5% more immediate
cardiotoxicity. Daunorubicin and mitoxantrone may also cause
cardiotoxicity. Irinotecan 35% suffer from severe diarrhea.
Etoposide causes leukopenia at 10-14 days recovering at 3
weeks and diarrhea in 55% who receive the drug orally.
Hormonal Agents
 Agents: Tamoxifen, raloxifene, faslodex, letrozole, anastrazole,
flutamide, nilutamide, bucalutamide, goserelin, leuprolide.
 Mechanism of Action: Tamoxifen, raloxifene and faslodex block the
estrogen receptor. Letrozole and anastrazole inhibit the production of
estrogen by inhibiting aromatase.
 Flutamide, nilutamide and bucalutamide block the androgen receptor
and goserelin and leuprolide over stimulate the gonadotropin releasing
hormone receptor (GRH) thereby inhibiting the release of GRH.
Hormonal Agents
 Toxicity: The anti-androgens may cause impotence,
gynecomastia, muscle wasting, bone loss, fatigue. Tamoxifen
causes an increase risk of endometrial cancer and
thromboembolism.
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Faslodex may cause osteoporosis and increased risk of
thromboembolisms. Raloxifene, thromboembolisms.
 The aromatase inhibitors may cause bone thinning and severe
joint pain. The GRH inhibitors may initially cause cardiac
ischemia, and edema. Later they may cause fatigue, impotence,
muscle wasting and bone loss.
Biologicals
 Agents: Trastuzumab, bevacizumab, cetuximab, gefitinib
 Mechanism of action: Trastuzumab is an antibody that inhibits
the her2/neu receptor. Bevacizumab is an antibody that inhibits
vascular endothelial growth factor. Gefitinib is a small molecule
that inhibits the epidermal growth factor receptor. Cetuximab is
an antibody that also inhibits the epidermal growth factor
receptor.
 Toxicity: Trastuzumab is cardiotoxic in 5% of patients. Long
term effects are not known.
 Bevacizumab may cause hypertension and bowel perforation
(ovarian cancer).
 Gefitinib and cetuximab cause a skin rashes and occasionally
elevated liver enzymes.
Standard Regimens for Prostate Cancer
 Hormonal Treatment (considered first)
 A) Luprolide with one of the following: Flutamide, nilutamide,
bucalutamide
 B) Goserelin with one of the following: Flutamide, nilutamide,
bucalutamide
 Chemotherapy (if hormonal treatment fails)
 A) Docetaxel and Prednisone
 B) Mitoxantrone and Prednisone
Standard Regimens for Breast Cancer
A) Doxorubicin, Cyclophosphamide followed by Paclitaxel .
B) Doxorubicin, Cyclophosphamide followed by Docetaxel
C) Methotrexate, Cyclophosphamide, 5-Fluorouracil followed by
Taxane
D) Carboplatin and Taxane
Add Trastuzumab for her2/neu positive breast cancer.
Add Tamoxifen or Letrozole for estrogen receptor positive breast cancer
Breast Cancer
Standard Regimens for Colon Cancer
A) (FOLFOX) Folinic acid, 5-fluorouracil,oxaliplatin
B) (FOLFIRI) Folinic acid, 5-flourouracil,irinotecan
C) (CAPOX) Capecitabine, oxaliplatin
Add cetuximab , bevacuzimab, gefitinib
Colon Cancer
Standard Regimens for Lung Cancer
Non-Small Cell Lung Cancer
A) Cisplatin, gemcitabine
B) Cisplatin, docetaxel
C) Cisplatin, etoposide
Consider Bevacizumab
Small Cell Lung Cancer
A)
Cisplatin, etoposide
B)
Cyclophosphamide, doxorubicin, and vincristine
Leukemia Treatment
Acute Lymphocytic Leukemia
Induction
Prednisone, L-asparaginase, and vincristine
Consolidation
Methotrexate and 6-mercaptopurine
Acute Myelocytic Leukemia
Induction
Daunomycin, cytosine arabinoside, etoposide
Consolidation
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Cytosine – arabinoside (ARA-C) and etoposide
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Cytosine – arabinoside (ARA-C) and mitoxantrone