|
Chemotherapy |
Pages Below:
|
Principles
Side EffectsShort term
Long term
Regimens
CHEMOTHERAPY
OF CANCER
Cancer refers to a set of diseases that manifest
uncontrolled proliferation, loss of function due to lack of the capacity to
differentiate, invasiveness and the ability to metastasise. It is a disease that
arises as a result of a series of genetic changes in the cell, the main genetic
lesions being inactivation of tumour supressor genes or the activation of
oncogenes. Principles of cancer therapy is to cure, or if this is not possible,
to provide palliation for the patients. Many cancers are effectively eradicated
with surgical excision and/or radiotherapy, however, the problem arises when
there is considerable invasion, spread and metastasis. This is when a systemic
approach is required. Chemotherapy:- ·
cancer therapy using cytotoxic drugs ·
main method of treatment for few cancers
(testicular ca, haematogenous ca), but increasingly used as adjuvant therapy to
surgery. ·
basis of chemotherapy is based on inhibiting
cell proliferation, thus most effective against rapidly dividing cells
(including normal cells). This is "Gompertzian Kinetics" ·
selectivity of drugs occurs as higher proportion
of cells in cancer is undergoing division than in normally proliferating tissue ·
some drugs are 'phase specific' (work on cells
in specific part of cell cycle) and others are 'cycle specific' (work on cells
in any part of cell cycle) Cytotoxic
drugs have small therapeutic window (small difference between minimum effective
dose of drug and maximum dose tolerated by patient) and thus pose many side
effects. Common side effects of chemotherapeutic drugs:- ·
Nausea and vomiting (especially female, <50
years old, those who experience motion sickness). Treat with 5HT3 antagonist and
dexamethasone ·
Alopecia (rapidly dividing hair follicles
targeted by drugs). Treat with refrigerated caps that lower skin temperature and
thus follicle proliferation ·
Infertility as germ cells are chemosensitive ·
Bone marrow suppression. Cytotoxic drugs will
also kill the rapidly dividing haemopoietic cells in the bone marrow. This
results in patient being susceptible to infection (treated by antibiotics).
Solution is bone marrow transplant or parental administration of bone marrow
growth factors (colony stimulating factors) ·
Hyperuricaemia that will cause gout and renal
failure Types
of chemotherapeutic drugs:- 1) Alkylating agents ·
have 2 functional groups that readily form
covalent bonds with DNA bases ·
form intrastrand or interstrand crosslinks that
distort DNA helix or prevent strand separation respectively ·
prevent cell division ·
cycle specific cytotoxic drug ·
cyclophosphamide
-treat chronic lymphocytic leukaemia (CLL), lymphomas and solid tumours
like
breast ca
-iv or oral
-metabolised in liver to active form acrolein (may cause complication
heamorrhage cystitis)
-usually used in combination with 5-Fluorouracil and methotrexate (CMF)
·
Chlorambucil
-treat CLL, non-Hodgkin's lymphoma, Hodgkin's lymphoma and ovarian ca
-oral
-few side effects (except for common ones) ·
Busulphan
-treat chronic myeloid leukaemia
-oral
-additional side-effects are hyperpigmentation of skin and occasionally
pulmonary fibrosis 2)Anti-metabolites ·
interfere with DNA synthesis ·
drug incorporate with new nuclear material or
combine with vital cellular enzymes to inhibit purine and pyrimidine synthesis,
thus prevent cell division ·
S-phase specific ·
Methotrexate
-treat acute lymphatic leukaemia, non-Hodgkin's lymphoma and choriocarcinoma
-competitively inhibits dihydrofolate reductase enzyme and thus prevent
the regeneration
of FH4 that is needed for the conversion of deoxyuridylic acid to
deoxythymidylate (needed for DNA synthesis)
-oral, iv, im or intrathecally
-contraindicated in renal impairment as drug is mainly excreted by
kidney, in hepatic impairment
-often used in combination (CMF)
-drug interactions with aspirin and other salicylates as they displace
methotrexate
from protein bound state; thereby increase adverse
effects of methotrexate ·
5-Fluorouracil
-treat breast ca and colon ca
-converted to 5-fluorodeoxyuridylic acid (5-F-dUMP) which inhibits
thymidylate
synthetase
-thymidylate synthetase converts deoxyuridylic acid (dUMP) to
deoxythymidylic acid (dTMP)
-drug reduce availability of dTMP and thus prevents DNA synthesis
-iv admin but may be used topically for certain skin lesions ·
Cytarabine
-treat acute leukaemia
-antipyrimidine; interfere with pyrimidine synthesis
-iv, sc, or intrathecally ·
Mercaptopurine
-maintenance therapy for acute leukaemias
-an antipurine that impairs the synthesis of purine nucleotides
-unclear mechanism
-lower dose administered if used with allopurinol (prevent breakdown of
mercaptopurine) 3)Cytotoxic antibiotics ·
Doxorubicin
-most widely used
-treat acute leukaemias, lymphomas, breast ca, ovarian ca and lung ca
-anthracycline
-intercalate (slip between neighbouring base pairs) and cause partial
unwinding of double helix. Produces single stranded and double stranded breaks
in DNA and also inhibits topoisomerase II (enzyme involved in cleavage,
unwinding and rejoining of DNA strands during synthesis) and thus inhibits DNA
and RNA synthesis
-S-phase specific
-high dose cause additional side effect of cardiomyopathy and heart
failure
-administered by iv and also by bladder instillation. Administration to
patient with pre-existing cardiac disease should be monitered ·
Bleomycin
-treat lymphomas, testicular teratomas and squamous cell carcinoma
-binds to DNA and degrade them by causing chain fragmentation
-iv or im
-cause little bone marrow suppression (myelosuppression)
-additional side effects are skin rashes and pulmonary fibrosis ·
Dactinomycin
-mainly used to treat children ca
-intercalates in mior groove of DNA and interferes with the movement of
RNA polymerase, thus preventing transcription
-iv
-cell cycle specific 4. Vinca
alkaloids ·
are plant derivatives ·
bind to tubulin and prevent its polymerisation
into microtubules. Thus prevent spindle formation that retract the chromosomes
into daughter cells in mitosis ·
M-phase specific ·
Vincristine
-treat acute leukaemia, lymphomas, breast ca and lung ca
-additional side effect of peripheral and /or autonomic neuropathy
-only iv ·
Vinblastine
-treat lymphomas and testicular teratomas
-cause more bone marrow suppression
-less neurological toxicity
-only iv 5. Others ·
include etoposide, taxol, cisplatin and hormones ·
Etoposide
-derived from mandrake root
-treat small cell carcinoma of bronchus, lymphomas and testicular ca
-inhibits cell's mitochondrial function and nucleoside transport and may
inhibit
topoisomerase II
-oral or slow iv
-common side effects ·
Taxol
-derivative of yew tree bark
-treat leukaemias, testicular ca and ovarian ca
-bind to tubulin and stabilise them (prevent them from becoming
depolymerised)
thus prevent cell to undergo mitosis
-M-phase specific ·
Cisplatin
-platinum compound
-treats ovarian tumour and especially curative for testicular ca (used in
combination with bleomycin and etoposide)
-has alkylating agents
-becomes activated when enters cell, and then forms adducts with DNA
bases. Causes intrastrand cross-linking
-iv admin.
-additional side effects include nephrotoxicity, ototoxicity and
peripheral
neuropathy,
papilloedema and cerebral blindness
-cell cycle specific ·
Hormones
-Prednisolone; inhibits cell division by interfering with DNA synthesis.
Used to treat leukaemias, lymphomas and breast ca
-Tamoxifen; is an oestrogen antagonist that is used to treat
postmenopausal metastatic breast ca
that are oestrogen receptor positive. Drug will prevent further stimulatory
effect of oestrogen on cancer cells. Side effects are predisposition to
endometrial ca
-Buserelin; is a gonadotrophin-releasing hormone analogue that will
inhibit
luteinizing hormone (LH)
secretion thus suppress the release of testosterone, hence treating prostatic ca |
|
|