Transcript CANCER CHEMOTHERAPY

CANCER CHEMOTHERAPY
General Principles of Action of
Anticancer Drugs
A. Treatment strategies
B. Treatment regimens and scheduling
C. Problems associated with chemotherapy
A. Treatment strategies
1. Goal of treatment
2. Indications for treatment
3. Tumor susceptibility and growth cycle
i. Cell-cycle specificity
ii. Tumor growth rate
B. Treatment regimens and scheduling
1. Log kill
2. Pharmacologic sanctuaries
3. Treatment protocols
a. Combination of drugs
b. Advantages of drug combinations
c. Treatment protocols
C. Problems associated with chemotherapy
1. Resistance
2. Multidrug resistance
3. Toxicity
a. Common adverse effects
b. Specific adverse effects
c. Minimizing adverse effects
d. Treatment-induced tumors
I. ANTIMETABOLITES
Drug Class
Mechanism of
Action
Adverse
Effects
Therapeutic
Uses
Methotrexate
MTX inhibits
dihydrofolate reductase
and deplete FH4,
leading to inhibition of
thymidylate and purine
synthesis.
•Nausea, vomiting,
•Diarrhea, stomatitis,
•Myelosupression,
•Renal damage
•Hepatotoxicity
•Pulmonary toxicity
Acute lymphocytic
leukemia
Burkitt lymphoma
Breast cancer
Crohn disease
Rheumatoid arthritis
6-Mercatopurine
Both drugs are
activated by
hypoxanthine –guanine
Phosphoribosyl
transferases to toxic
nucleotide that inhibit
several enzymes
involved in purine
metabolism
•Bone marrow
•depression
•Nausea, vomiting&
•Diarrhea
•Hepatotoxicity
Acute leukemia
Chronic myelocytic
leukemia
Allopurinol inhibits
metabolism of 6-MP
and increases its
effect and toxicity
6-Thioguanine
Fludarabine
Cladribine
Both drugs inhibit DNA
synthesis by interfering with
ribonucleotide reductase and
DNA polymerase
Nausea, vomiting,
diarrhea
Myelosuppression
Fever, edema
Neurologic toxicity
Chronic lymphocytic
Leukemia
Non-Hodgkin
Lymphoma
Hairy cell leukemia
• In the body, 6-MP is converted to the corresponding
ribonucleotide. 6-MP ribonucleotide is a potent inhibitor
of the conversion of a compound called inosinic acid to
adenylic acid. Without adenylic acid, DNA cannot be
synthesized.
• It also inhibits the conversion of inosinic acid to xanthylic
acid that is necessary for the synthesis of guanylic acid.
Fludrabine
5’-phosphate of
2-fluoroarabinose
5-Fluorouracil
Cladribine
2-chorodeoxy
adenosine
Drug Class
Mechanism of
Action
Adverse Effects
5 – FU is biotransformed
to 5-fluoro-2’deoxyuridine-5’monophosphate (5FdUMP), which inhibits
thymidylate synthase
leading inhibiting DNA (but
not RNA) synthesis.
Nausea, vomiting,
diarrhea, ulceration of
oral & GIT mucosa,
alopecia
Capecitabine
It is converted in-vivo by
Thymidine
Phosphorylase
into 5-fluorouracil
Similar to 5-fluorouracil
Cytarabine
It is a Pyrimidine
antimetabolite. The
drug is activated by
kinases to Ara-CTP, an
inhibitor of DNA
polymerases.
Fluorouracil
(5-FU)
(cytosine arabinoside)
It is most specific for
the S phase of cell
cycle.
Gemcitabine
(Pyrimidine analog)
It is phosphorylated by the
enzyme deoxycytidine
kinase to the di- and
triphosphate nucleotide forms,
which replaces cytidine &
inhibit DNA synthesis
Bone marrow depression
Anorexia
Severe myelosuppression
Nausea, vomiting,
diarrhea
Hepatic dysfunction
Myelosuppression
Nausea, vomiting,
alopecia
Flu-like syndrome
Therapeutic
Uses
Slowly growing solid
tumors: Colorectal,
breast, ovarian,
pancreatic & gastric
carcinomas.
As an adjuvant
With levamisole
Metastatic breast
cancer
Colorectal cancers
Acute myeloid
leukemia in
combination with 6-TG
and daunorubicin
Pancreatic cancer
Lung cancer
II. Antibiotics
Drug Class
Dactinomycin
(Actinomycin D)
Mechanism of
Action
It intercalates DNA, forming 1.
a stable dactinomycin-DNA
complex. The complex
interferes with DNA2.
dependent RNA
polymerase
Adverse
Effects
Therapeutic Uses
Bone marrow
Melanoma & Pediatric
tumors as Wilms’
tumor (neoplasm of
the kidneys that
occurs in children)
depression
Nausea, vomiting,
diarrhea, alopecia
Doxorubicin,
Daunorubicin
Idrarubicin
Epirubicin
These anthracyclines can
intercalate between base
pairs, inhibit topoisomerase
II, and generate free
radicals. They block the
synthesis of RNA and DNA
and cause DNA strand
scission. They must be
given intravenously
They are metabolized in
the liver & excreted in the
bile & urine (red color)
Bone marrow depression
Bleomycin
It generates free radicals
which bind to DNA, cause
strand breaks, and inhibit
DNA synthesis.
Pulmonary fibrosis
2. Allergic reaction
3.Little
myelosuppression
GI distress &
Alopecia
Doxurubicin causes
cardiac toxicity
Dexrazoxane
(derivative of EDTA
and chelates iron),
may protect against
cardiotoxicity.
Doxorubicin is used
in Hodgkin’s disease
Breast cancer
Lung cancer
Ovarian cancer
Daunorubicin is used
in the treatment of
acute leukemias
Idrarubicin is used for
certain types of acute
leukemia
Testicular tumors
Hodgkin’s disease
III. Alkylating Agents
Drug Class
Adverse
Effects
Therapeutic Uses
1.
Nausea, vomiting
Mechloroethamine
spontaneously converts in
the body to a reactive
cytotoxic product
2.
Myelosuppression
3.
Immunosuppression
4.
Alopecia
1. Hodgkin's disease
(MVPP)
2. Solid tumors as
breast, prostate and
ovarian carcinoma
They can be given orally
Cyclophosphamide is a
prodrug that undergoes
metabolic activation to produce
the active compounds:
phosphoramide mustard, and
acrolein
Reaction of the phosphoramide
mustard with DNA is considered
to be the cytotoxic step.
Toxic metabolites of
cyclophosphamide & ifosfamide
are excreted in the urine
1. Urinary tract
hemorrhagic cystitis (due to
a toxic metabolite;
acrolein). So, patients
should be hydrated and
treated with sodium 2mercaptoethane
sulfonate (MESNA).
This interacts with acrolein
forming non toxic complex.
Bone marrow depression
Nausea, vomiting, alopecia
testicular atrophy
Neurotoxicity
Mechanism of
Action
Mechloroethamine It is administered only IV
Cyclophosphamide
Ifosfamide
Burkitt lymphoma
Non-Hodgkin’s
lymphoma
Breast & ovarian
cancer
Alkylating Agents (Cont.)
Drug Class
Nitrosoureas:
Carmustine
Lomustine
Semustine
Mechanism of
Action
They are highly
lipophilic and can
cross BBB, making
them useful in the
treatment of brain
tumors.
Temozolomide
(orally)
Both undergo
biotransformation to
an active metabolite,
Dacarbazine (IV) methylhydrazine.
Temozolamide
inhibits the repair
enzyme, O6 –
guanine-DNAalkyltransferase.
Adverse
Effects
Hematopoietic
depression
Aplastic anemia,
Renal toxicity
Pulmonary fibrosis
Myelosuppression
(neutropenia and
thrombocytopenia)
Nausea, vomiting
Therapeutic Uses
Brain tumors
Temozolamide
approved for
use against
astrocytomas
Both drugs
used in
melanoma
IV. Microtubule Inhibitors
Drug Class
Mechanism of
Action
Adverse
Effects
Therapeutic Uses
Vinca Alkaloids:
Vincristine
Vinblastine
They bind to the
microtubular protein,
tubulin and blocks the
ability of tubulin to
polymerize to form
microtubules,
preventing spindle
formation in mitosing
cells and causing cell
arrest at metaphase.
Both produce: vomiting,
diarrhea, and alopecia
For Vincristine:
Peripheral neuropathy
(Parasthesia, loss of
reflexes)
Paralytic ileus
For Vinblastine:
Myelosuppression
GI distress
Alopecia
Vincristine:
acute leukemias,
lymphomas,
Wilms’ tumor
Vinblastine:
Hodgkin’s disease
and lymphomas
and testicular
carcinoma
Paclitaxel
They bind reversibly to
the - tubulin subunit,
but unlike vinca
alkaloid, they promote
polymerization and
assembly of nonfunctional mitotubules.
This results in death of
the cell.
Neutropenia
Peripheral neuropathy
Fluid retention
(Docetaxe)
Hypersensitivity
Advanced ovarian
cancer
Metastatic breast
cancer
Docetaxel
Dynamic instability of microtubules
V. Steroid Hormones & Their Antagonists
A. Hormones
1. Glucocorticoids: Prednisone
2. Estrogens: Fosfestrol
3. Progestogens: Megestrol & Medroxyprogesterone.
B. Hormone Antagonists
1. Anti-estrogens: Tamoxifen & Toremifene
2. Anti-androgens: Flutamide & Cyproterone
C. Aromatase Inhibitors
1. Aminoglutethimide
2. Anastrozole & Letrozole (nonsteroidal)
3. Exemestane
D. Gonadotropin–releasing hormone analogs
1. Leuprolide
2. Goserelin
3. Nafarelin
VI. Monoclonal Antibodies
Trastuzumab
Trastuzumab (Herceptin®) is a humanized monoclonal antibody that
acts on the HER2/neu (erbB2) receptor. Its principal use is as an
anticancer therapy in breast cancer patients whose tumors
overexpress this receptor. It is administered either once a week or
once every three weeks IV.
Rituximab
• Rituximab is a genetically engineered chimeric monoclonal antibody
used in the treatment of B cell non-Hodgkin's lymphoma, B cell
leukemia, and some autoimmune disorders.
• The antibody binds to the cluster of differentiation 20 (CD20). CD20
is widely expressed on B-cells and plays a role in activating cell
cycle initiation and differentiation. The CD20 antigen is expressed
on nearly all B cell non-Hodgkin lymphomas but not in other bone
marrow cells.
VII. Others
1. Cisplatin & Carbopaltin
Cisplatin
2. L-Asparaginase
3. Etoposide & Teniposide
4. Procarbazine
5. Imatinib
Imatinib is used mainly for the treatment of chronic myeloid leukemia and other
types of tumors. It acts as a signal transduction inhibitor, used specifically that
inhibits tumor tyrosine kinase (TK) activity. Imatinib is specific for the TK
domain in abl (the Abelson proto-oncogene). In chronic myelogenous leukemia,
the Philadelphia chromosome leads to a fusion protein of abl with bcr
(breakpoint cluster region), termed bcr-abl. As this is now a continuously active
tyrosine kinase, imatinib is used to decrease bcr-abl activity.
Philadelphia chromosome
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