Transcript Antineoplastic Agents

ANTINEOPLASTIC
AGENTS
BY:
Israa Eltayib
Cancer pathogenesis and cancer
chemotherapy: general principles
• The term cancer refers to a malignant
neoplasm(new growth)
• Cancer arises as a result of genetic changes,
the main genetic lesions being :
1. Inactivation of tumor suppressor genes(e.g.
p53)
2. The activation of oncogenes(mutation of the
normal genes controlling cell division and
other processes).
Cancer pathogenesis and cancer
chemotherapy: general principles
• Cancer cell have four characterstics that
distinguish it from normal cells:
1. Uncontrolled proliferation
2. Loss of function because of lack capacity to
differentiate
3. Invasiveness
4. ability to metastasise
Cancer pathogenesis and cancer
chemotherapy: general principles
• Cancer cells have uncontrolled proliferation
because of changes in :
1. Growth factor and there receptors
2. Intracellular signalling pathway, particularly
those controlling the cell cycle and apotosis
3. Telomerase expression
4. Tumor related angiogenesis
Cancer pathogenesis and cancer
chemotherapy: general principles
• Most anticancer agents are antiproliferative;
affecting cell division, most damage the DNA
and thereby initiate apoptosis.
• But have no inhibitory effect on invasiveness,
loss of differentiation or ability to metastasizes
Cancer cell cycle and anticancer
agents
• Some anticancer agents exert their actions on cell
undergoing cycling (cell cycle specific [CCS] drugs),
and others (cell cycle non specific[CCNS]drugs) kill
the tumor in both cycling and resting phase of the
cell cycle (although cycling cell are more
sensitive).
• CCS drugs are usually most effective when cells
are in specific phase of the cell cycle
• Both types of drugs are more effective when a
large prpotion of the tumor cells are proliferating
The log kill hypothesis
The log kill hypothesis
Cancers that are very difficult to
treat with chemotherapy
• Solid tumors are very difficult to be treated with
chemotherapy alone and need other modality
of treatment like surgery and/or radiotherapy as
opposed to hematological malignancies that
shows good response to chemotherapy alone.
• Examples of solid tumors includes :
1. Colon and stomach
2. Lung
3. Late stage breast cancer
4. Uterus
5. Pancreatic cancer
Cancers that are very difficult to
treat with chemotherapy
• Solid tumors are difficult to be treated with
chemotherapy because the growth rate of this
tumors falls as the neoplasm grows. This
partly because the tumor partially necroses as
it outgrows its ability to maintain its blood
supply, and partly because not all the cells
proliferate continuously.
Cancers that are very difficult to
treat with chemotherapy
• Solid tumors cells can be divided in to three
compartments
1. Compartment A consists of dividing cells
2. Compartment B consists of resting cells
3. Compartment C consists of cells that are no
longer able to divide but contribute to the
volume
• Essentially only the cells in compartment A,
which constitute around 5% of solid tumors, are
susceptible to the main current cytotoxic drug.
Cancers that are very difficult to
treat with chemotherapy
• Compartment C do not constitute any
problem, but the existence of compartment B
that make the chemotherapy difficult because
those cells are not very sensitive to
chemotherapy and are liable to re-entre
compartment A following chemotherapy.
Toxicity and side Effects of
Antineoplastic Agents
• They affect rapidly dividing normal cells and
are thus likely to depress bone marrow, impair
healing, damage to GI epithelium, and depress
growth.
• Virtually all of them cause severe nausea and
vomiting which has been affecting the patient
compliance to completing a course of
chemotherapy.
• Most can cause sterility, hair loss and
teratogenicity
Toxicity and side Effects of
Antineoplastic Agents
• They can be carcinogenic by themselves in
certain circumstances
• Rapid cell destruction also entails extensive
purine catabolism, and urate can precipitate in
the renal tubules and cause kidney damage.
• some compounds have particular toxic effect
that are specific for them.
Resistance to chemotherapy
Resistance to chemotherapy may develop by several
mechanisms:
1. Decrease in the amount of drug uptake by cancer cell
e.g. Methotrexate
2. Increase in the amount of drug removed by cancer
cells. (Transporters=P-glycoprotein).e.g. Vinblastine
,doxorubicin, bleomycin
3. Decrease or alteration in target molecule sensitivity –
this is caused by mutation in the molecule targeted by
the drug e.g.Methotrexate,Mercaptopurine.
4. Increase in DNA repair ability of the cell via an
increased expression of DNA repairing enzymes.e.g.
Alkylating agent
Anticancer Drugs
There are two Major Groups of Anticancer
Drugs:
1) Cytotoxic Drugs (largest group)
• Alkylating agents
• Antimetabolites
• Antitumor antibiotics
• Plant alkaloids
• Miscellaneous cytotoxic drugs
Anticancer Drugs
2) Hormones and hormone antagonists
These are among the best-tolerated
chemotherapeutics because they target
specific receptors, and thus only specific cell
types e.g. Tamoxifen
Cell cycle
Scientists have determined that cell
cycle can be divided into:.
Gap 0 (G0): There are times when a
cell will leave the cycle and quit
dividing. This may be a temporary
resting period or more permanent.
An example of the latter is a cell
that has reached an end stage of
development and will no longer
divide (e.g. neuron).
Gap 1 (G1): Cells increase in size in
Gap 1, produce enzymes needed
for DNA synthesis
Mitosis or M Phase: Cell growth and
S Phase: To produce two similar
protein production stop at this stage
daughter cells, the complete DNA
in the cell cycle. All of the cell's
instructions in the cell must be
energy is focused on the complex
duplicated. DNA replication occurs
and orderly division into two similar
during this S (synthesis) phase.
daughter cells.
Gap 2 (G2): It is the gap between DNA
synthesis and mitosis, the cell will
continue to grow and produce new
proteins & RNA.
CYTOTOXIC DRUGS
I-Alkylating Agents
• used in cancer treatment that attaches an alkyl
group (CnH2n+1) to DNA.
• The alkyl group is attached to the guanine base of
DNA, at the number 7 nitrogen atom of the purine
ring.
• Since cancer cells, in general, proliferate faster and
with less error-correcting than healthy cells, cancer
cells are more sensitive to DNA damage — such as
being alkylated.
• Alkylating agents are used to treat several cancers.
I-Alkylating Agents
• However, they are also toxic to normal cells
(cytotoxic), leading to damage, in particular in
cells that divide frequently, as those in the
gastrointestinal tract, bone marrow, testicles
and ovaries, which can cause loss of fertility.
Most of the alkylating agents are also
carcinogenic.
• Hyperthermia is especially effective at
enhancing the effects of alkylating agents
Mechanism of action
• Dialkylating agents can react with two
different 7-N-guanine residues, and, if these
are in different strands of DNA, the result is
cross-linkage of the DNA strands, which
prevents uncoiling of the DNA double helix.
• If the two guanine residues are in the same
strand, the result is called limpet attachment
of the drug molecule to the DNA.
• Busulfan is an example of a dialkylating agen
Mechanism of action
• Monoalkylating agents can react only with
one 7-N of guanine.
• Limpet attachment and monoalkylation do not
prevent the separation of the two DNA
strands of the double helix but do prevent
vital DNA-processing enzymes from accessing
the DNA. The final result is inhibition of cell
growth or stimulation of apoptosis, cell
suicide.
I-Alkylating Agents
Subgroups of Alkylating Agents
1.
2.
3.
4.
Nitrogen mustards
Nitrosoureas
Alkyl sulfonates
Platinum Coordination Compounds
1-Nitrogen Mustards
a- Cyclophosphomide
• The most commonly used alkylating agent.
• It is inactive until metabolized in the liver to give
aldophophamide, which is then converted to
phosphormide mustard and acrolein (which
cause bladder damage that can be ameliorated
by Mensa or N-acetylcystiene).
• It has a profound effect on lymphocytes ,so it
can be used as immune -suppressant
• Imporatant toxic effect include nausea, bone
marrow suppression and hemorrhagic cystitis
Cyclophosphomide
1-Nitrogen Mustards
b- Estramustine
• Is combination of chlormethine (mustine) with
an estrogen
• It has both cytotoxic effect and hormonal
action, and generally used for treatment of
prostatic cancer
• other nitrogen mustard include Melphalan
and chlorambucil.
2-Nitrosoureas
• Example of this group include carmustine and
lomustine
• They can cross the blood brain barrier ,so they
can be used for brain and meningeal tumors
• Most nitrosoureas have a severe cumulative
depressive effect on the bone marrow that
start 3-6 weeks after initiation of treatment
3-Busulfan
• It has selective action on the bone marrow,
depressing the formation of granulocyte and
platelets in low dosage and RBCs in higher
dosage.
• It has little effect on lymphoid tissues or the
gastrointestinal tract.
• It is used in chronic granulocytic leukemia.
4-Platinum compounds
Cisplatin
• Forms crosslinks within DNA strands.
• Cis-platin is not really an “alkylating” agent, but
since it operates via the same mechanism as the
alkylating agents, it is placed within that group.
• It has revolutionized the treatment of germ cells
tumors
• It has low myelotoxicity but causes severe nausea
and vomiting (which can be prevented by
Ondansetron), and can be nephrotoxic.
• Other adverse effect include tinnitus and hearing
loss ,peripheral neuropathy and anaphylactic
reaction.
II-Antimetabolites (CCS)
• An antimetabolite is a chemical with a similar
structure to a metabolite required for normal
biochemical reactions, yet different enough to
interfere with the normal functions of cells,
including cell division.
• Antimetabolites are used in cancer treatment,
as they interfere with DNA production and
therefore cell division and the growth of
tumors (mainly in S-phase specific).
• They are classified into:
1- Folate antagonists.
2- Purine analogues.
3- Pyrimidine analogues .
1- Folate antagonists
• Methotrexate: inhibits dihydrofolate
reductase, preventing generation of
tetrahydrofolate interfering with thymidylate
synthesis.
• Methotrexate is taken up in to the folate
carrier and, like folate, is converted to the
polyglutamate form.
• Normal cells affected by high doses can be
“rescued₺ by folinic acids.
• Unwanted effects are mylosupression and
possible nephrotoxicity.
1- Folate antagonists
2- Purine analogues
Mercaptopurine
• It is a purine analogue and once enter the cell,
it is converted to 6-MP-ribosephophate and
can be incorporated into RNA&DNA resulting
in non functioning RNA & DNA &finally
inducing cell cycle arrest and apoptosis.
2- Purine analogues
• Azathioprine: non-enzymatically cleaved to 6 M P that acts as a purine analogue and
inhibits DNA synthesis
• Fludarabine: in its triphosphate form inhibits
DNA polymerase and is myelosuppressive.
• Penostatin: inhibits adenosin deaminase- a
critical pathway in purine metabolism
3- Pyrimidine analogues
• 5-flurouracil (5-FU):It act as a uracil analogue,
it is transformed inside the cell into 5-FU
deoxynucleotide which compete with
deoxyuridine DUMP for thymidylate synthase
leading to inhibition of dthymidine
monophosphate DTMP synthesis inhibition of
DNA synthesis
• Cytarabine: In its triphosphate form inhibits
DNA polymerase.
• They are potent myelosupressive.
5-flurouracil (5-FU)
Cytarabine
III-Antitumor antibiotics (CCNS)
• This is a widely used group of drugs that
mainly produce their effects through direct
action on DNA.
• As a rule, they should not be given together
with radiotherapy, as the cumulative burden
of toxicity is very high.
III-Antitumor antibiotics
• 1-Doxorubicin: Inhibits DNA and RNA synthesis;
the DNA effect is mainly through interference
with topoisomerase II action. Unwanted effects
include nausea, vomiting, myelosuppression
and hair loss.It is cardiotoxic in high doses.
• 2-Dactinomycin: It inhibits transcription by
binding to DNA at the transcription initiation
complex and preventing elongation by RNA
polymerase,it can also interfere with DNA
replication.
III-Antitumor antibiotics
• 3-Bleomycin: Causes fragmentation of DNA
chains. It acts on non-dividing cells. Unwanted
effects include fever, allergies, mucocutanous
reactions and pulmonary fibrosis,there is
virtually no myelosuppression .
• 4-Mitomycin: Is activated to give an alkylating
metabolite ,it can cause Lung fibrosis may
occur. If these lung problems do occur,
corticosteroids may provide effective therapy.
IV-Plant alkaloids (Phase specific)
1-The vinca alkaloids
• Vincristine & vinblastine (M-phase):
Vincristine gntiibihni nilubut ot sdnib
.serutcurts elubutorcim fo notiaziremylop
sisotim stserra selubutorcim eht fo notipursiD
erofereht sdiolakla acniv ehT .esahpatem ni
gnidulcni sepyt llec gnidivid yldipar lla tceffa
dna muilehtipe lantisetni osla tub ,sllec recnac
worram enob.
IV-Plant alkaloids (Phase specific)
1-The vinca alkaloids
• Vincristine & vinblastine (M-phase): The Vinca
alkaloids are relatively non-toxic. Vincristine has
very mild myelosupressive activity but cause
(sensory changes), abdominal pain and muscle
weakness fairly frequently.
• Vinblastine is less neurotoxic but causes
leucopenia, while Vindesine has both moderate
myelotoxicity and neurotoxicity
• All members of the group can cause reversible
IV-Plant alkaloids (Phase specific)
2-Taxanes
• Paclitaxel & docetaxel: paclitaxel hyperstabilizes microtubule structure (freez them).
Paclitaxel binds to the β subunit of tubulin ,the
resulting microtubule/paclitaxel complex does
not have the ability to disassemble.
• This adversely affects cell function because
the shortening and lengthening of
microtubules is necessary for their function
IV-Plant alkaloids (Phase specific)
3-Etoposide
• Chemically it is deriven from podophyllotoxin,
a toxin found in the mandrake root.
• An inhibitor of the enzyme topoisomerase II,
cause breaks in the DNA inside the cancer
cells and prevent them from further dividing
and multiplying.
• It also inhibit mitochondrial function .
IV-Plant alkaloids (Phase specific)
4-Campothecins
• Irinotecan: it works by inhibition of
topoisomerase II
• It has relatively very few adverse effects.
V-Miscellaneous cytotoxic drugs
1-Crisantaspase
• It is a preparation of asparaginase which kills
cancer cells by breaking down (L−asparagine)
that is necessary for survival and growth of
certain tumors e.g. acute lymphoblastic
leukemia ALL.
• Fortunately, normal cells are able to
synthesize Asparagine .
• The drug has fairly selective action, with very
little suppressive effect in bone marrow, GI
mucosa and hair follicle.
• It may cause nausea and vomiting and
anaphylactic reaction.
V-Miscellaneous cytotoxic drugs
2-Mitotan
• Effective in the treatment of adrenocortical
carcinoma.
• As a chemical, mitotane resembles the
insecticides DDD and DDT, although mitotane
does not harm people as these do. Scientists
do not understand why, but the drug causes
damage to the adrenocortex in such a way as
to be helpful for some patients with
adrenocortical tumors.
• In addition, mitotane restricts the ability of
the gland to produce steroids.
V-Miscellaneous cytotoxic drugs
3-Monoclonal antibodies
• Rituximab and Alemtuzumab lyse Blymphocyte and is used for B-cell lymphomas.
unwanted adverse effect include fever, chills,
hypotension and hypersensitivity reaction.
• Trastuzumab: (Herceptin) targets epidermal
growth factor receptor (HER2)and is used for
breast cancer
V-Miscellaneous cytotoxic drugs
4-Biological response modifier
• Those are agents that are used to inhance host
immune response against cancer cells
• Examples include interferone-α and it is
pegylated derivative ) are used in the treatment
of solid tumor and lymphoma, and
Aldeslukin(recombinant interleukin-2) is used in
some cases of renal tumors.tretinoin (a form of
vitamin A) is a powerful inducer of differentiation
in leukaemic cells and is used as an adjunct to
chemotherapy to induce remission
V-Miscellaneous cytotoxic drugs
2- Hormones and
hormone antagonists
I-Glucocorticoids
• Glucocorticoids such as prednisolone and
dexamathasone have marked inhibitory
effects on lymphocyte proliferation and are
used in the treatment of leukaemias and
lymphomas.
• Their ability to lower ICP, and to mitigate some
of the side effects of anticancer drugs, makes
them useful as supportive therapy when
treating other cancers, as well as in palliative
care.
II-Gonadal hormone antagonist
Tamoxifen
• Tamoxifen selectively inhibits the effects of
estrogen on breast tissue, while selectively
mimicking the effects of estrogen on bone (by
increasing bone mineral density) and uterine
tissues
• Unwanted effects are similar to menopause,
potentially more serious are hyperplastic
events in the endometrium, which may
progress to malginant changes, and the risk of
thromboembolism.
III-gonadotrophin-releasing
hormome(GnRH)analogs
• Leuprolide, Goserelin, and Nafarelin are
GnRH agonist, effective in prostatic carcinoma
and premenopausal breast cancer.
• When administered in constant doses so as to
maintain stable blood levels, they inhibit
release of pituitary luteinizing hormone(LH)
and follicle stimulating hormone(FSH).
• Leuprolide can cause bone pain,
gynecomastia, impotence and testicular
atrophy
IV-Aromatase inhibitors
• Anastrozole and Letrozole inhibit the
conversion of androstenedione (androgenic
precursor) to estrone (estrogenic precursor).
• both drugs are used in advanced breast
cancer.
General approaches to cancer
therapy
• Kill or remove malignant cells: cytotoxic drugs,
surgery, irradiation, and radioactive agent
• Inactivate components of oncogene signaling
pathway: inhibitors of growth factors
receptors (e.g. receptors tyrosine kinase)
• Restore function of tumor suppressor : gene
therapy
General approaches to cancer
therapy
• Employ tissue-specific proliferation inhibitors:
estrogen, antiestrogen, androgen, antiandrogen,
glucocorticoids and GnRH
• Inhibit tumor growth, invasion, metastasis:
inhibitors of angiogenesis.
• Enhance host immune response: cytokine-based
therapies ,gene therapy-based approach, cellbased approach
• Reverse drug resistance: inhibitors of multidrug
resistance transport.
Good luck