4.
Chemotherapy is the treatment of cancer with
one or more cytotoxic anti-neoplastic drugs
("chemotherapeutic
agents")
as
part
of
a standardized regimen.
Chemotherapy may be given with a curative intent
or it may aim to prolong life or to palliate
symptoms.
5.
Certain chemotherapeutic agents also have a role in
the
treatment
of
other
conditions,
including
ankylosing
spondylitis,
multiple
sclerosis,
Crohn's
disease, psoriasis, psoriatic arthritis, systemic lupus
erythematosus,
rheumatoid
arthritis, and scleroderma.
conditioning regimens in SCT
◦ Cyclophosphamide ,busalfan ,melphlan
6.
7.
8.
9.
Combined modality chemotherapy is the use of drugs
with other cancer treatments, such as radiation
therapy or surgery.
Induction chemotherapy is the first line treatment of
cancer with a chemotherapeutic drug. This type of
chemotherapy is used for curative intent.
Consolidation chemotherapy is the given after
remission in order to prolong the overall disease free
time and improve overall survival. The drug that is
administered is the same as the drug that achieved
remission.
Intensification chemotherapy is identical to
consolidation chemotherapy but a different drug than
the induction chemotherapy is used.
10.
Combination chemotherapy involves treating a
patient with a number of different drugs simultaneously.
The drugs differ in their mechanism and side effects.
The biggest advantage is minimising the chances of
resistance developing to any one agent. Also, the drugs
can often be used at lower doses, reducing toxicity.
Neoadjuvant chemotherapy is given prior to a local
treatment such as surgery, and is designed to shrink the
primary tumor. It is also given to cancers with a high risk
of micrometastatic disease.
Adjuvant chemotherapy is given after a local
treatment (radiotherapy or surgery). It can be used
when there is little evidence of cancer present, but there
is risk of recurrence.
11.
Maintenance chemotherapy is a repeated lowdose treatment to prolong remission.
Salvage chemotherapy is potentially curative high
dose ,compination regimens,given in patient with
failed or recurrent after many curative regimens .
palliative chemotherapy is given without curative
intent, but simply to decrease tumor load and
increase life expectancy.
12. since these drugs act by inhibiting cell division, the
most common side effects are those that occur in
areas of the body where cell replication occurs, such
as
A.
the GI mucosa (nausea, vomiting, diarrhœa),
B. the
bone marrow (myelosuppression causing
leukopænia and other blood dyscrasias), and
C.
hair follicles (alopecia).
D.
Most antineoplastics have less effects on those cells
that are non-dividing (kidney, heart) and effects on
these organs are often the result of damage to
portions of the cell other that DNA.
13.
Originally derived from mustard gas used in the war, They are
so named because of their ability to alkylate many
molecules, including proteins, RNA and DNA.
This causes "mistakes" in the DNA that may result in
mispairing, substitutions, or excision.
This leads to a form of programmed cell death called
apoptosis.
Alkylating agents are non-cell-cycle specific
the higher the dose, the more damage to DNA
14. The subtypes of alkylating agents are
Nitrogen mustards
include mechlorethamine, cyclophosphamide, melphalan
and chlorambucil.
Alkylsulphonate Busulfan
Nitrosoureas
include carmustine (BCNU), lomustine (CCNU)
Tetrazines includes dacarbazine
others
include
Cisplatin
and
derivatives
include cisplatin,carboplatin and oxaliplatin
Non-classical alkylating agents include procarbazine .
15. Two DNA bases that are cross-linked by a nitrogen
mustard. Different nitrogen mustards will have different
chemical groups (R). The nitrogen mustards most
commonly alkylate the N7 nitrogen of guanine (as shown
here) but other atoms can be alkylated
16.
Meclorethamine
◦ Uses -- (MOPP) for Hodgkin's disease and mycosis fungoids.
◦ Toxicity -- lacrimation, local damage (irritation, sloughing,
necrosis) if extravasation occurs (sodium thiosulphate)
Cyclophosphamide
◦ Uses -- Lymphoma, chronic leukæmia, numerous carcinomas,,
breast cancer, multiple myeloma, neuroblastoma and
retinoblastoma in children.
◦ Toxicity -- pulmonary fibrosis,cardiotoxicity. Other toxicities
include a syndrome of inappropriate ADH (SIADH), ridging of
nails, and hæmorrhagic cystitis. The hæmorrhagic cystitis may
be diminished by the administration of 2-mercaptoethane
sulphonate or MESNA, which donates sulphydryl groups to
inactive the drug.
17.
Ifosfamide
◦ Uses -- Germ cell testicular cancer, sarcomas and salvage
therapy in lymphoma( ICE )
◦ Toxicity -- is nephrotoxicity and
neurotoxicity
deathNephrotoxicity may be diminished by 2-MESNA.
(coma,
Melphalan
◦ Uses -- Multiple myeloma, breast and ovarian cancers
Chlorambucil
◦ use-- Chronic lymphocytic leukemia, non-Hodkin's
lymphoma and macroglobulinæmia
◦ Toxicity -- Relatively side effect free, Pulmonary toxicity
is rare.
Alkylsulphonate(Busulfan)
◦ Use -- Chronic granulocytic leukæmia
◦ Toxicity -- pulmonary fibrosis and
syndrome .
Addison-like
18.
Carmustine (BCNU)
chloronitrosourea
and Lomustine (CCNU)-- a
◦ Uses -- Hodkin's and non-Hodkin lymphoma, brain tumours,
multiple myeloma (mini –BEAM), malignant melanoma,mycosis
fungoides (LOCAL)
◦ Toxicity -- Pulmonary fibrosis, Liver and Renal Failure.
Triazene (Dacarbazine)
◦ Uses -- Malignant melanoma, Hodkin's lymphoma(ABVD), soft
tissue cancers, and sarcomas
Toxicity -- GI upset, mild to moderate BMS, flu-like syndrome
19. ◦ Mechanism of Action -- These agents are bioactivated through
substitution of chloride ions for hydroxyl groups. The active
moiety then interacts with DNA, forming both inter- and intrastrand links (especially to the DNA base guanine)
◦ Uses – salvage therapy for lymphoma(DHAP,ESHAP),Ovarian,
testicular, bladder, head, neck, and endometrial cancers
◦ Toxicity -- Ototoxicity and Neurotoxicity nephrotoxicity (this
may be attenuated by hydration and diuresis), and electrolyte
disturbances (probably mediated by the liberated chloride ions).
Carboplatin
◦ Uses –salvage therapy for lymphoma(ICE) The same as cisplatin
Toxicity -- Fewer toxicities that cisplatin.
20.
Mechanism of Action -- Procarbazine methylates
DNA, essentially acting in a manner similar to the
alkylating agents.
Additionally, free radical
formation may contribute to the action of
procarbazine. Both of these actions will decrease
DNA, RNA, and protein synthesis.
Use -- Hodkin's lymphoma(MOPP)
Toxicity -- neurotoxicity (including behavioural
changes), and a disulfiram-like reaction.
21.
22. 1.
Folate Antagonists -- Methotrexate
◦ Mechanism of Action -- Methotrexate inhibits dihydrofolate
reductase
◦ Methotrexate is primarily active during the S phase of the cell
cycle
◦ The toxic effects of methotrexate may be reversed by the
administration of leucovorin, which is a fully reduced folate cofactor. Leucovorin "rescue“
◦ Uses -- Acute lymphocytic leukæmia,aggressive lymphoma
(MACOP-B) choriocarcinoma, mycosis fungoides, osteogenic
sarcoma, and breast.
◦ Toxicity -- pneumonitis. Chronic side effects (seen with
methotrexate as a immunosuppressant in rheumatoid arthritis
or psoriasis) include hepatic fibrosis and cirrhosis.
23.
24.
5-Fluorouracil (5-FU) and Floxuridine -- these drugs are
analogues of uridine
◦ Mechanism of Action -- Both of these agents are metabolised in
vivo to F-UTP and F-dUTP which inhibit RNA and DNA
synthesis respectively
◦ Uses --Breast, GI, ovarian, cervical, bladder, prostate, and
pancreatic cancers and hepatoma.
Cytarabine (cytosine arabinoside) -- a cytosine analogue
◦ Mechanism of Action -- activated to the nucleotide form to
substitute for CTP, inhibiting DNA chain elongation, as previously
described.
Uses -- Acute granulocytic and lymphocytic leukæmias.
◦ Toxicity -- DLT = Neurotoxicity (especially in older adults).
25.
purine antagonists appear to substitute for
guanine or adenosine to decrease/inhibit metabolic
reactions that are necessary to form the guanine or
adenine that will be incorporated into DNA.
6-Mercaptopurine Uses -- Leukæmias
◦ Toxicity -- jaundice (33%), and hyperuricæmia and
hyperuricosuria
Azathioprine -- this drug is a 6-MP derivative that
is used for its immunosuppressive effects. The
mechanism of action is the same as 6-MP.
26.
Fludaribine -- an adenine analogue
◦ Mechanism of Action -- Fludaribine inhibits DNA polymerase.
◦ Uses -- Chronic lymphocytic leukæmia
◦ Toxicity --chills, fever, neurotoxicity, and pulmonary toxicity.
Cladribine -- an adenine analogue
◦ Uses -- Cladribine is the drug of choice of hairy cell leukæmia
Pentostatin
◦ Mechanism of Action -- Pentostatin inhibits adenosine
deaminase to increase intracellular levels of adenosine and
deoxyadenosine nucleotides.
◦ Uses -- hairy cell leukæmia and chronic lymphocytic leukæmia
◦ Toxicity -- neurotoxicity, nephrotoxicity. Also, , rash, and
hepatotoxicity.
27.
28.
29.
Mechanism of Action -- The vinca alkaloids block
cellular mitosis by directly binding to and inhibiting
tubulin formation, specifically during metaphase.
Vinblastine
◦ Uses -- metastatic testicular cancer and lymphoma(ABVD).
◦ Toxicity -- SIADH (rare), alopecia, and sloughing/necrosis
with extravasation.
Vincristine
◦ Uses -- Hodkin's and non-Hodkin lymphoma, pediatric
leukæmias, numerous solid tumours
◦ Toxicity -- Neurotoxicity
30.
Paclitaxel (Taxol) and Docetaxel
◦ Uses -- Ovarian and breast cancers
◦ Toxicity -- These agents may also cause bradycardia (early) and
silent ventricular tachycardia (late).
Epipodophyllotoxins -Mechanism of Action -- The epipodophyllotoxins form a ternary
complex with DNA and topoisomerase II, causing double-strand
breakage. (Late S,G2 phase)
Etoposide
◦ Uses -- Testicular, breast, and small-cell lung cancers, salvage
therapy non-hodkin lymphoma (ICE,ESHAP,mini BEAM),
leukæmia, and Kaposi's sarcoma.
Teniposide
◦ Uses -- Primarily used for refractory acute lymphocytic leukæmia in
children
31.
32.
Anthracycline Antibiotics
Mechanism of Action –
DNA intercalation,
preventing DNA and RNA synthesis, single and double stranded
breaks (via topoisomerase II).
form free radicals (ferrous ion and oxygen are necessary catalysts
for their formation) which may directly damage DNA, RNA, or
cellular components, accounting at least in part for the cytotoxic
effects of the drugs.
◦ anthracycline antibiotics form free radicals that responsible for the
cardiotoxicity associated with these drugs, through damage to the
contractile structures of the myocardium. by the administration of
an anti-oxidant (alpha-tocopherol) or an iron chelating agent
(dexrazoxane).
33.
Daunorubicin (daunomycin, rubidomycin)
Doxorubicin (doxomycin)
Uses -- Broader spectrum of activity, used in several
solid tumours
Idarubicin
Mitoxantrone -- these are derivatives of the
anthracycline antibiotics
◦ Uses -- Primarily used for leukæmias
◦ Toxicity -- cardiotoxicity (manifest early as arrhythmia, late as
congestive failure.
◦ Mechanism of Action -- The anti-neoplastic effects of
mitoxantrone are due to DNA intercalation. It does not exhibit
the degree of free radical formation and therefore essentially
lacks the cardiotoxic effects of others in the class.
34.
Actinomycin D (Dactinomycin)
◦ Mechanism of Action -- Dactinomycin intercalates with DNA to
prevent DNA transcription by RNA polymerase,Dactinomycin
causes strand breaks by decreasing topoisomerase II activity.
◦ Uses -- Rhabdomyosarcoma, Wilm's tumour, Choriocarcinoma,
testicular cancer, and Kaposi's sarcoma
Bleomycin
◦ Mechanism of Action -- Bleomycin binds to DNA and generate free
radicals. CCS DRUG (G2 PHASE)
◦ Uses -- Squamous cell carcinoma, œsophageal cancer, testicular
and ovarian cancer, and both Hodgkin's(ABVD) and non-Hodgkin
lymphoma(MACOP-B).
◦ Toxicity
-Pulmonary
fibrosis,
cutaneous
toxicity
(hyperpigmentation, hyperkeratosis, erythema, ulceration).
35.
Mitomycin
◦ acts as an alkylating agent to decrease DNA
synthesis, increase cross-linking of DNA, and to cause
single-strand breakage.
◦ Uses -- cervical, colorectal, breast, bladder, and lung
cancers.
◦ Toxicity -- Hæmolytic/uremic syndrome (due to
endothelial damage of the red cells and renal
epithelium), pulmonary fibrosis and cardiotoxicity.
36.
Mechanism of Action -- Most normal cells can synthesis
the amino acid asparagine. However, many neoplastic
cells lack this capability ,thereby depriving the
neoplastic cell of asparagine and thus inhibiting protein
synthesis, which leads to cell death by apoptosis.
Uses -- leukæmias.
Toxicity -- Hypersensitivity, However decreases in
protein synthesis may lead to insulin deficiency and
clotting factor deficiency.
Clinical Note -- methotrexate prior to L-asparaginase
increases the cytotoxic activity and side effect
37.
Mechanism of Action -- Hydroxyurea inhibits the
enzyme ribonucleotide reductase, thereby inhibiting
the
conversion
of
ribonucleotide
to
deoxyribonucleotides. This inhibits DNA synthesis. Its
actions are specific for the G1 to S phase of the cell cycle.
Uses -- Leukæmias, polycythemia vera (overproduction
of erythrocytes), malignant melanoma. Hydroxyurea is
also used in the treatment of sickle cell anæmia to
decrease hæmolysis. This effect is mediated by an
increase in the synthesis of hæmoglobin F (probably by
a separate mechanism, possibly increased expression of
the Hgb F gene).
38.
39.
40.
41. Acquired drug-resistant models possess multiple drugresistance mechanisms. These mechanisms include:
(a) decreased intracellular concentration of the drug
characteristic of overexpression of drug transporters;
(b) alterations in the drug target such as point mutations or
overexpression of the target;
(c) increased detoxification of the drug such as glutathione
conjucation;
(d) changes in the repair of DNA damage induced by the drug
(e) alterations in the cell cycle checkpoint such as p27or p21;
(F) changes in the ratio of pro and antiapoptotic BCL-2 family
members
