03-Anti-Cancer Drugs - FST PDF
03-Anti-Cancer Drugs - FST PDF
03-Anti-Cancer Drugs - FST PDF
Overview
Introduction
Malignant disease accounts for a high proportion
of deaths in industrialised countries.
Introduction
Cancer occurs after normal cells have been
transformed into neoplastic cells through alteration of
their genetic material and the abnormal expression of
certain genes. Neoplastic cells usually exhibit
chromosomal abnormalities and the loss of their
differentiated properties. These changes lead to
uncontrolled cell division and many result in the
invasion of previously unaffected organs, a process
called metastasis.
Advances in Cancer Chemotherapy
Treatment options of cancer:
Non-clinical Research:
1.Anticancer Drug Screen:
in vitro:tumor cell culture, tumor
inhibitor/kill test
in vivo:animal xenograft model e.g.Ehrlich
ascites tumor, S180 lymphosarcoma
2. Pharmacodynamics, pharmacokinetics and
toxicology test
The Main Step of Anticancer
Drug Research
Clinical Research:
Phase 1 clinical trial
Phase 2 clinical trial
Phase 3 clinical trial
Phase 4 clinical trial
The Main Step of Anticancer
Drug Research
Phase 1 clinical trial
In Phase 1 clinical trials, researchers test a new
drug or treatment in a small group of people
(20-80) for the first time to evaluate its
safety, determine a safe dosage range, and
identify side effects.
• TOLERANCE
• PHARMACOKINETICS
The Main Step of Anticancer
Drug Research
Busulfan [Myleran]
Indications:
Busulfan is administered orally to treat chroic
granulocytic leukemia and other
myeloproliferative disorders.
Adverse Effects:
Busulfan produces advers effects related to
myelosuppression. It only occasionally produces
nausea and vomitting. In high doses, it produces
a rare but sometimes fatal pulmonary
fibrosis, ”busulfan lung”.
Alkylating Agents——Thiotepa
General Characteristics:
Antimetabolites are S phase-specific
drugs that are structural analogues of
essential metabolites and that interfere
with DNA synthesis.
Myelosuppression is the dose-limiting
toxicity for all drugs in this class.
Classification of Antimetabolites
5-Fluorouracil (5-FU)
Indications:
Fluorouracil is exclusively used to treat
solid tumors, especially breast, colorectal,
and gastric tumors and squamous cell
tumors of the head and neck.
Antimetabolites——
Pyrimidine Antagonists
5-Fluorouracil (5-FU)
Adverse Effects:
Fluorouracil may cause nausea and vomiting,
myelosuppression, and oral and gastrointestinal
ulceration. Nausea and vomitting are usually mild.
With fluorouracil, myelosuppression is more
problematic after bolus injections, whereas
mucosal damage is dose-limiting with continuous
infusions.
Antimetabolites——
Pyrimidine Antagonists
Cytarabine
Indications:
Cytarabine has a narrow clinical spectrum and is
primarily used in combination with daunorubicin or
thioguanine for the treatment of acute
nonlymphocytic leukemia.
Adverse Effects:
High doses of cytarabine can damage the liver,
heart, and other organs.
Antibiotics
Classification of Antibiotics:
Adriamycin (Anthracyaline Antibiotics)
Mitomycin C
Bleomycin
Actinomycin D
Antibiotics
Actinomycin D:
Actinomycin D intercalates DNA and thereby
prevents DNA transcription and messenger RNA
synthesis.
The drug is given intravenously, and its clinical
use is limited to the treatment of trophoblastic
(gestational) tumors and the treatment of
pediatric tumors, such as Wilms’ tumor and
Ewing’s sarcoma.
Antibiotics
Bleomycin:
Mechanism:
The drug has its greatest effect on neoplastic
cell in the G2 phase of the cell replication
cycle.Although bleomycin intercalates DNA, the
major cytotoxicity is believed to result from
ironcatalyzed free radical formation and DNA
strand breakage.
Indications:
It is useful in Hodgkin’s and non-Hodgkin’s
lymphomas, testicular cancer, and several other
solid tumors.
Adverse Effects:
Bleomycin produces very little myelosuppression.
The most serious toxicities of Bleomycin are
pulmonary and mucocutaneous reactions.
Anti-Cancer Plant Alkaloids
Tubulin-Binding Agents
Vinca Alkaloids: The cellular mechanism of
action of vinca alkaloids is the prevention of
microtubule assembly, causing cells to arrest
in the late G2 phase by preventing formation
of mitotic filaments for nuclear and cell
division.
Anti-Cancer Plant Alkaloids
Tubulin-Binding Agents
Vinca alkaloids:
Vinblastine,vincristin, vindesine and vinorelbine are all
alkaloids derived from the periwinkle plant (Vinca rosea).
Indications:
Vinblastine is used in combination with Bleomycin
and Cisplatin for metastatic testicular tumors.
Vincristine is used in combination with prednisone
to induce remission in childhood leukemia.
Vinorelbine is used to treat non-small-cell lung
cancer and breast cancer.
Anti-Cancer Plant Alkaloids
Tubulin-Binding Agents
Paclitaxel:
Taxanes enhance all aspects of tubulin
polymerization, an action that is the opposite to
that of vinca alkaloids, but they are also
cytotoxic, emphasizing the dynamic importance of
tubulin polymerization as a target for cytotoxic
drugs.
Paclitaxel, Taxotere
Anti-Cancer Plant Alkaloids
Interfere the Function of Ribosome:
Cephalotaxus Alkaloids :
Harringtonine
Homoharringtonine
Platinum Compound
Cisplatin:
Mechanism of Action:
Cisplatin binds to guanine in DNA and
RNA, and the interaction is stabilized by
hydrogen bonding. The molecular
mechanism of action is unwinding and
shortening of the DNA helix.
Platinum Compound
Cisplatin:
Indications:
Cisplatin has efficacy against a wide range of
neoplasms. It is given intravenously as a first-
line drug for testicular, ovarian, and bladder
cancer, and it is also useful in the treatment of
melanoma and a number of other soild tumors.
Adverse Effect:
Cisplatin produces relatively little
myelosuppression but can cause severe nausea,
vomiting, and nephrotoxicity.
Platinum Compound
Carboplatin:
Indication:
Carboplatin has a similar spectrum of
activity, but it is approved only as a
second-line drug for ovarian cancer.
Hormones
Estrogens:
Estrogens inhibit the effects of endogenous
androgens and androgen-dependent metastatic
prostatic carcinoma. Diethylstilbestrol is usually
the agent of choice.
Cardiac and cerebrovascular complications and
carcinoma of the male breast are potential
adverse effects.
Hormones
Progenstins:
Progestins are useful in the management of
endometrial carcinoma and back-up therapy for
metastatic hormone-dependent breast cancer.
Hormones
Antiestrogen: Tamoxifen
Tamoxifen is the drug of choice in
postmenopausal women with or recovering from
metastatic breast cancer. It is most effective in
patients who have estrogen receptor-positive
tumors.
Tamoxifen is also used as adjunvctive therapy to
oophorectomy to leuprolide or goserelin in
premenopausal women with estrogen receptor-
positive tumors.
Hormones
Androgens:
Androgen activity in breast cancer is similar to
that of estrogens, perhaps for the same
mechanistic reasons.
Virilizing effects and hepatic toxicity make them
unacceptable to most patients.
Fluoxymesterone is the most widely used agent.
Danazol has use in hematology in aplastic anemia
and congenital anemias.
Hormones
Glucocorticoids:
They are integral components of curative therapy
for acute lymphoblastic leukemia, non-Hodgkin’s
lymphoma, and Hodgkin’s disease.
Glucocorticoids have essential roles in the
prevention of allergic reaction, emesis control,
relief of intracranial hypertension or spinal cord
compression in neurologic complications, and pain
relief.
Problems With Cancer
Chemotherapy
Drug Resistance
Drug Toxicity
Drug Resistance
De novo Resistance
Acquired Resistance
Multidrug Resistance (MDR)
Drug Resistance
De novo resistance:
De novo resistance can be de novo genetic (i.e.
the cells are initially inherently resistant), or can
arise because drugs are unable to reach the
target cells because of permeability barriers
such as the blood-brain barrier.
Drug Resistance
Acquired Resistance:
Acquired drug resistance may result from
genomic mutations, such as the induction or
deletion of enzymes involved in drug inactivation
or drug activation, respectively.
Drug Resistance
Immunosuppressive Agents:
Act to suppress immune mechanisms and are used
to treat autoimmune diseases or to prevent graft
rejection following tissue transplantation.
Immunopotentiator :
Enhance antitumor immunity and are used to
treat neoplastic disease.
Recombinant Interferons and Cytokines.