L38 chemotherapeutics 2018 revised

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Cancer Chemotherapy
Andy Catling, PhD
Department of Pharmacology
MEB 5th floor
What is Cancer ?
A. Cancer = simplistically an imbalance in cell
proliferation and cell death (apoptosis)
B. Properties of cancer cells:
 Persistent proliferation of cells that differentiate
poorly or not at all; rapid vs slow growth.
 Lack contact inhibition.
 Able to invade and destroy neighboring tissue.
 Metastases: cancer cells that leave primary tumor,
travel through lymphatic and blood vessels and
colonize distant sites; poor prognosis.
Treatment
1. Radiation
2. Surgery
When neoplasms are disseminated and/or not
amenable to surgery, or as a supplement to
surgery and radiation:
1.
2.
3.
4.
5.
“Conventional” Chemotherapy
Hormonal therapy
Rationally designed therapy
Immunotherapies and Prophylaxis
Combinations of above
Challenges of Chemotherapy
A. Failure to detect disease early
B. 100% kill required – multiple rounds of
treatment, multiple agents, significant toxicity
C. Drug resistance
1. Intrinsic: loss/mutation of tumor suppressors
2. Acquired: tumor responds to single drug initially, but
over time develops resistance
Challenges of Chemotherapy
D. Narrow therapeutic index/toxic side effects
1.
2.
3.
4.
5.
6.
7.
8.
Bone marrow suppression (often dose limiting)
Increased risk of infection, febrile neutropenia
Mucositis throughout GI tract
Nausea, vomiting and cachexia
Alopecia
Damage to reproductive system
Neurotoxicity
DNA damage – treatment can be mutagenic,
carcinogenic and teratogenic
Strategies to maximize efficacy and
minimize side-effects
A. Combination therapy to reduce likelihood of
resistance
B. Rationally-designed therapy tailored to
patient’s molecular abnormalities – e.g. CML,
specific types of breast cancer
C. Harness immune system to fight cancer
D. Optimization of dosing and route
E. Intermittent therapy to allow normal cell
recovery (esp. bone marrow)
F. Supportive therapy
Chemotherapeutics
M
Treatment
G2
G1
1. Radiation
2. Surgery
When neoplasms are disseminated and/or not
amenable to surgery, or as a supplement to
surgery and radiation:
1. Chemotherapy
2. Hormonal therapy
3. Immunotherapy
4. Combinations of above
S
Cell death (apoptosis) can
occur at any phase in the cycle.
Phase
Function
~% time
G1
RNA and Protein synthesis
40
S
DNA synthesis
39
G2
Tetraploid; prepare for mitosis
19
M
Mitosis; diploid daughter cells
2
G0
Quiescent; differentiation or re-enter cell cycle
-
Purine and Pyrimidine Synthesis
Ribonucleotides
Antimetabolites,
CCS
Deoxyribonucleotides
Microtubule
Inhibitors, CCS
S
DNA intercalating/
damaging agents,
CCNS
Alkylating Agents,
CCNS
DNA
G2 M
DNA
Topoisomerase
Inhibitors, CCS
RNA
Proteins
Rationally designed
drugs
Cell Cycle Specificity
 Cell Cycle Specific (CCS)
chemotherapeutic drugs
active only in specific cell
cycle phases
 Inhibitors of DNA synthesis (Sphase) e.g. antimetabolites
 Inhibitors of mitosis (M-phase),
e.g. microtubule inhibitors
 Cell Cycle Nonspecific
(CCNS)
chemotherapeutic drugs
that target both resting
and dividing cells
 Inhibitors of gene
expression/DNA damaging
agents e.g. alkylating
agents, antibiotics,
estrogen/androgen
antagonists
Purine and Pyrimidine Synthesis
Ribonucleotides
Antimetabolites,
CCS
Deoxyribonucleotides
Microtubule
Inhibitors, CCS
S
DNA intercalating/
damaging agents,
CCNS
Alkylating Agents,
CCNS
DNA
G2 M
DNA
Topoisomerase
Inhibitors, CCS
RNA
Proteins
Rationally designed
drugs
Antimetabolites
Mechanism of Action:
structural analogs of endogenous molecules
required for the synthesis of e.g. DNA,
interfere with DNA synthesis
S phase specific
Most effective for rapidly proliferating tumors,
esp. leukemias, lymphomas
All cause myelosuppression
Antimetabolites cont.
1. Methotrexate (MTX)
 Widely used, most effective for pediatric
ALL, choriocarcinoma (75-90% cure)
 Structurally related to folic acid, required for
synthesis of DNA/RNA
 Administer Leucovorin (folate supplement)
to partially protect from cytotoxicity
Purine and Pyrimidine Synthesis
Ribonucleotides
Antimetabolites,
CCS
Deoxyribonucleotides
Microtubule
Inhibitors, CCS
S
DNA intercalating/
damaging agents,
CCNS
Alkylating Agents,
CCNS
DNA
G2
M
DNA
Topoisomerase
Inhibitors, CCS
RNA
Proteins
Rationally designed
drugs
Microtubule Inhibitors
Microtubule Inhibitors
1.
Vinca Alkaloids





2.
Taxanes





Vincristine & Vinblastine
Vincristine is used to treat pediatric leukemias (with
corticosteroids) and solid tumors, adult lymphomas
Vinblastine used to treat testicular cancer (with bleomycin and
cisplatin), lymphomas
CCS = M-phase
Neurotoxicity with vincristine, little with vinblastine
Paclitaxel & Docetaxel
Cisplatin-resistant solid tumors
CCS = M-phase
Peripheral neuropathy
Acquired resistance due to MDR-1 gene
Purine and Pyrimidine Synthesis
Ribonucleotides
Antimetabolites,
CCS
Deoxyribonucleotides
Microtubule
Inhibitors, CCS
S
DNA intercalating/
damaging agents,
CCNS
Alkylating Agents,
CCNS
DNA
G2
M
DNA
Topoisomerase
Inhibitors, CCS
RNA
Proteins
Rationally designed
drugs
Topoisomerase Inhibitors
 Topoisomerase is required for mitosis.
Etoposide
• Testicular cancer (combination therapy with
cisplatin and bleomycin)
• Small cell lung carcinoma
• Acute non-lymphocytic leukemia can
develop in acute lymphocytic leukemia
patients
 Resistance due to MDR-1 gene.
MDR1 and Acquired resistance
Intracellular drug targets
e.g. Taxane
Taxane pumped out
of cell: effectiveness of
Taxane therapy decreases as
MDR1 expression increases.
Taxane
Effective therapy
MDR1
TUMOR CELL
CYTOPLASM
Most importantly – effectiveness
of other drugs recognized by MDR1
(e.g. Etoposide) is decreased in parallel!
Cell Cycle Specificity
 Cell Cycle Specific (CCS)
chemotherapeutic drugs
active only in specific cell
cycle phases
 Inhibitors of DNA synthesis (Sphase) e.g. antimetabolites
 Inhibitors of mitosis (M-phase),
e.g. microtubule inhibitors
 Cell Cycle Nonspecific
(CCNS)
chemotherapeutic drugs
that target both resting
and dividing cells
 Inhibitors of gene
expression/DNA damaging
agents e.g. alkylating
agents, antibiotics,
estrogen/androgen
antagonists
Purine and Pyrimidine Synthesis
Ribonucleotides
Antimetabolites,
CCS
Deoxyribonucleotides
Microtubule
Inhibitors, CCS
S
DNA intercalating/
damaging agents,
CCNS
Alkylating Agents,
CCNS
DNA
G2
M
DNA
Topoisomerase
Inhibitors, CCS
RNA
Proteins
Rationally designed
drugs
DNA Intercalating/Damaging Drugs
A. Antibiotics
Mechanism of Action
 Intercalate into DNA and prevent transcription
 Cause DNA strand breaks
 Generally cell cycle non-specific
DNA Intercalating/Damaging Drugs
1. Bleomycin
 Widely used antibiotic
• Squamous carcinomas of the head, neck and lungs
(combination therapies with cisplatin and others)
• Curative for germ cell tumors of the testis
(with cisplatin/vinblastine or cisplatin/etoposide)
• Highly effective for germ cell tumors of the ovary
 Minimally myelo- and immunosuppressive
 Toxicity:
• Pulmonary fibrosis related to total dose
• Cutaneous toxicity (hyperkeratosis, ulceration)
• Rare fulminant reaction in lymphoma patients
Purine and Pyrimidine Synthesis
Ribonucleotides
Antimetabolites,
CCS
Deoxyribonucleotides
Microtubule
Inhibitors, CCS
S
DNA intercalating/
damaging agents,
CCNS
Alkylating Agents,
CCNS
DNA
G2
M
DNA
Topoisomerase
Inhibitors, CCS
RNA
Proteins
Rationally designed
drugs
Alkylating Agents
 Mechanism of Action:
 Highly reactive compounds that cause cross linking of
DNA
 Prevent gene expression; DNA damage causes
apoptosis
 Cell Cycle Nonspecific
 Dose limiting toxicity to bone marrow and
intestinal mucosa
 All are mutagenic/carcinogenic; can induce
leukemia
 Cells mutant for the tumor suppressor p53
have intrinsic resistance
Alkylating Agents cont.
A.
B.
C.
D.
Nitrogen Mustards
Platinum compounds
Nitrosoureas
Alkyl sulfonates
Alkylating Agents cont.
A. Nitrogen Mustards (relatives of WW1
mustard gases !)
Cyclophosphamide


Very broad spectrum
• Highly effective against Burkitt’s Lymphoma
• Adjuvant therapy after surgery for breast cancer
Toxicity:
• Potent immunosuppression
• GI ulceration
• Hemorrhagic cystitis
• Marked alopecia
• Nausea and vomiting
Alkylating Agents cont.
B. Platinum Compounds
Cisplatin and Carboplatin
 Cisplatin (with bleomycin, etoposide and
vinblastine) for testicular cancer (85% cure)
 Carboplatin (with paclitaxel or
cyclophosphamide) for ovarian cancer
 Nephrotoxicity (minimized with hydration and
diuresis), ototoxicity, severe nausea and vomiting
Intrinsic resistance and p53
DNA
Environmental insult,
normal cell
p53
Alkylating agent,
p53-positive tumor cell
p53
Alkylating agent,
p53-negative tumor cell
p53
Resistance to
therapy
Purine and Pyrimidine Synthesis
Ribonucleotides
Antimetabolites,
CCS
DNA intercalating/
damaging agents,
CCNS
Alkylating Agents,
CCNS
Deoxyribonucleotides
DNA
G2/M
Microtubule
Inhibitors, CCS
DNA
Topoisomerase
Inhibitors, CCS
RNA
Proteins
Rationally designed
drugs
Treatment
1.
2.
3.
4.
5.
“Conventional” Chemotherapy
Rationally designed therapy
Hormonal therapy
Antibodies and Immunotherapy
Combinations of above
Rationally Designed
Chemotherapeutics
Drugs targeted to the causative molecular
abnormality; becoming more common.
 Imatinib (Gleevec)




Inhibitor of the bcr-abl tyrosine kinase causative for,
and found only in, chronic myelocytic leukemia (+
some ALL)
Remarkably effective with few side effects
Low incidence of resistance
Mutations in bcr-abl causing resistance can be identified
and drug structure can be modified to overcome resistance
Purine and Pyrimidine Synthesis
Ribonucleotides
Antimetabolites
e.g. Methotrexate
Microtubule
inhibitors e.g.
Vincristine, Paclitaxel
Deoxyribonucleotides
S
Intercalating/damaging
agents e.g. Bleomycin
DNA
G2
M
DNA
Topoisomerase
inhibitors e.g.
Etoposide
RNA
Alkylating Agents
e.g. Cyclophosphamide,
Cisplatin
Proteins
e.g. Tyr kinase
Rationally Designed
Drugs e.g. Imatinib
Treatment
1.
2.
3.
4.
5.
“Conventional” Chemotherapy
Rationally designed therapy
Hormonal therapy
Immunotherapies and Prophylaxis
Combinations of above
Hormonal Agents
 Breast and prostate tumors frequently
require estrogen/androgen for
growth/survival
 Tumor cell growth/survival can be inhibited
by lowering hormone levels or antagonizing
hormone function
 Relatively minor side effects (no
myelosuppression, mucositis etc)
TARGET CELL
NUCLEUS
Hypothal.
ER/AR
GnRH
Gene
Expression
Pituitary
LH, FSH
ER/AR
Testes/
Ovaries
TARGET CELL
CYTOPLASM
Estrogen/Androgen
Hormonal Agents
 Anti-estrogens

First choice for hormonal therapy of estrogen receptor (ER)+
breast cancer (adjuvant and therapy of metastatic disease)
• Tamoxifen approved for breast cancer prevention in
women at high-risk (age, history, heredity)

Raloxifene, a drug used to treat osteoporosis, was found to
dramatically reduce the risk of invasive breast cancer.
• 2007, Raloxifene approved for breast cancer prevention
in women at high-risk (age, history, heredity)

Inhibit binding of estradiol to the ER and subsequent gene
transcription (less effective in premenopausal women due to
high circulating estrogen; ineffective in ER-negative tumors)

Toxicity: concerns re. endometrial cancer, otherwise relatively
minor
Hormonal Agents
 Anti-androgens

Useful in the treatment of prostate cancer
• Steroidal anti-androgens (e.g. cyproterone), inhibit androgen
binding to the AR
• Non-steroidal anti-androgens (e.g. bicalutamide), inhibit nuclear
translocation of the AR

Anti-androgens inhibit AR-dependent gene transcription

Toxicity: relatively minor
TARGET CELL
NUCLEUS
Hypothal.
ER/AR
GnRH
Pituitary
bicalutamide
tamoxifen
cyproterone
LH, FSH
Gene
Expression
ER/AR
Testes/
Ovaries
TARGET CELL
CYTOPLASM
Estrogen/Androgen
Treatment
1.
2.
3.
4.
5.
6.
Radiation
Surgery
Chemotherapy
Hormonal therapy
Immunotherapies and Prophylaxis
Combinations of above
Immunotherapy
Programmed Cell Death (PD) 1 protein therapies (2014);
allow immune system to tackle the tumor
Melanoma etc
Complex mechanism: in summary
antibodies to PD-1 (Nivolumab,
Pembrolizumab) allow T cells to
attack tumors that otherwise would
suppress T cell activity
Chimeric antigen receptor (CAR) T-cell therapy e.g. tisagenlecleucel (ALL, 2017)
(“living drug”)
Antibodies
Humanized monoclonal antibodies
 Rituximab
 Binds CD20 found on 90% of non Hodgkin’s lymphomas
 Sometimes conjugated with radioactive 131I
 For relapsed/refractory B cell non Hodgkin’s lymphomas
 Trastuzumab (Herceptin)
 Antibody to human epidermal growth factor receptor 2 (HER2)
 Approved for treatment (in combination with paclitaxel or
doxorubicin) of metastatic breast cancers over-expressing HER2
Major side effects: tumor lysis syndrome (Rituximab)
hypersensitivity
Prophylaxis
 Vaccines against Human Papilloma Viruses
 HPV 16 and 18 cause ~70% of cervical cancer and
~70% anal cancer
 HPV 31, 33, 45, 52, 58 cause ~20% of cervical cancer
 HPV 6, 11, 16 and 18 cause ~90% of genital warts
 Vaccines against a specific HPV are highly effective in
preventing disease caused by that specific virus
 Vaccines elicit humoral immune response to select
HPVs
 Quadrivalent (Gardasil; HPV 6, 11, 16, 18) 2006
 Divalent (Cervarix; HPV 16, 18) 2009
 Nonavalent (Gardasil 9; all types above) 2014
 Males and females may be immunized
Prophylaxis
Routine screening and intervention is still the
current standard of care for cervical cancer;
historically a 75% reduction in cervical cancer.
These vaccines do not protect against other causes
of cervical/anal cancer.
These vaccines do not protect against viruses a
person already has.
These vaccines do not treat existing cervical/anal
cancer.
Combination Therapies
Combinations of antimetabolites, alkylating agents, antibiotics etc – advantages:
kill cells in multiple phases of cycle
combining drugs with different mechanisms of resistance lowers risk of
acquired resistance
1.
MOPP regimen for Hodgkin’s disease




2.
(alkylating agent, less effective in p53-mutant cells)
(microtubule inhibitor, MDR-1 mediated drug efflux)
(alkylating agent)
(corticosteroid)
CMF regimen for breast cancer



3.
Mechlorethamine
Oncovin (vincristine)
Procarbazine
Prednisone
Cyclophosphamide
Methotrexate
Fluorouracil
(alkylating agent, less effective in p53-mutant cells)
(antimetabolite)
(antimetabolite)
ABVD regimen for Hodgkin’s




Adriamycin
Bleomycin
Vinblastine
Decarbazine
(intercalating agent)
(intercalating agent)
(microtubule inhibitor, MDR-1 mediated drug efflux)
(alkylating agent, less effective in p53-mutant cells)
Support Therapy
A. Filgrastim (Neupogen)

Granulocyte colony-stimulating factor, prophylaxis of
chemotherapy-induced neutropenia
B. Sargramostim (Leukine)

Granulocyte/macrophage colony-stimulating factor, aids
neutrophil recovery in AML patients
C. Pamidronate (Aredia)

Prevents hypercalcemia and bone resorption associated with
malignancy
D. Erythopoietin (Procrit) & Darbopoiten

E.
Leucovorin

F.
Stimulates bone marrow RBC production, treats anemia
resulting from myelosuppressive therapy
Folate supplement
Support therapies/lifesyle changes for nausea,
vomiting, other side effects of chemo.

http://www.cancer.gov/cancertopics/coping
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