UNIVERSITY OF LUSAKA

CANCER CHEMOTHERAPY
Principles of cancer chemotherapy
• the ultimate goal of cancer treatment is cure
• cure requires complete eradication of tumor cells
• if cure is not attainable, the goal is palliation
(alleviation of symptoms and avoidance of life
threatening toxicity)
• drug therapy is a balance between toxic effects
of drugs and their efficacy
• combination therapy is more efficacious than
single dug therapy in most cancers for which
chemotherapy is effective
 Principles of cancer chemotherapy…
• In combination therapy, agents with
qualitatively different toxicities and different
molecular sites and mechanisms of action are
usually combined at full doses; while those
with similar dose limiting toxicities can be
combined safely only by reducing the doses of
each
 Principles of cancer chemotherapy…
• Advantages of combination
- Provide maximum cell kill within the range of
tolerated toxicity
- May slow or prevent the development of drug
resistance
 Problems associated with cancer
chemotherapy
• Resistance
- Some neoplastic cells are inherently resistant to
most anticancer dugs (e.g. melanoma)
- some tumors acquire resistance to the cytotoxic
effects of the drugs particularly after prolonged
administration of low doses
- the development of drug resistance is minimized
by short term intensive intermittent therapy with
combination of drugs
 Problems associated with cancer
chemotherapy…
• Mechanism of resistance
- over-expression of genes for target proteins
- drug inactivation by tumor cells
- defective apoptosis (programmed cell death) in tumor
cells
- loss of receptors for hormonal anti-cancer agents
One of the best characterized mechanisms is over-
expression of the MDR-1 gene which codes for a cell
membrane transporter that causes efflux of certain
drugs (e.g. vinca alkaloids, taxanes, anthracyclines)
 Problems associated with cancer
chemotherapy…
• Toxicity
- The ideal chemotherapeutic drug would target
and destroy only cancer cells, unfortunately,
few such drugs exist
- therapy aimed at killing rapidly proliferating
cancer cells also effects normal cells
undergoing rapid proliferation e.g. buccal
mucosa, GIT mucosa, hair follicles, sperm
forming cells, bone marrow,
 Problems associated with cancer
chemotherapy…
• Common adverse effects include:
- Bone marrow suppression
- GIT injury (stomatitis, diarrhoea)
- fetotoxicity
- alopecia
- sterility
- carcinogenesis
- hyperuricaemia (due to DNA breakdown following cell
death)
- localized tissue injury
- nausea and vomiting
 Classes of Anti-cancer drugs
A. Anti-metabolites
B. Mitotic inhibitors
C. DNA cross-linking drugs and alkylating agents
D. Topo-isomerase inhibitors
E. Platinum complexes
F. Hormones
G. Miscellaneous
 Anti-metabolites

1. Folate antagonist
methotrexate- a folic acid analogue
- Inhibits dihydrofolate reductase and interferes
with thymidylate synthesis
- commonly responsive tumors: choriocarcinoma,
non-Hodgkin’s lymphoma, Burkitt’s lymphoma,
ovarian cancer, osteogenic sarcoma, head and
neck cancer
 Anti-metabolites…
Methotrexate
- Toxicity: mucosal ulceration, bone marrow
suppression, nausea and vomiting, renal
damage,
- Toxicity can be reduced by giving folinic acid
(tetrahydrofolate)
- increased toxicity with impaired renal
function
 Anti-metabolites…
2. Purine antagonist
a) 6-mercaptopurine (a purine analogue)
- Blocks de novo purine synthesis
- uses: acute leukemia
- Toxicity: mutagenic, myelosuppression,
immunosuppression
b) Thioguanine (a purine analogue)
- Blocks de novo purine synthesis
- Uses: leukemias
- Toxicity: myelosuppression, immunosuppression,
hepatotoxic, nausea/vomiting, diarrhea
 Anti-metabolites…
3. Pyrimidine antagonists
a) 5-fluoro-uracil
- Inhibits thymidylate synthetase, therefore,
inhibits DNA synthesis
- uses: GI tumor, breast cancer
- toxicity: mucositis, alopecia,
myelosuppression, diarrhoea, nausea and
vomiting, neurotoxicity
 Anti-metabolites…
b) Cytarabine
- Inhibits DNA synthesis by chain termination
when incorporated into DNA
- uses: acute leukemia, lymphomas
- toxicity: myelosuppression, nausea/vomiting,
stomatitis, hepatotoxic, skin rash, cerebella
and conjunctival toxicities at high doses,
 Anti-metabolites…
c) Gemcitabine
- Chain termination when incorporated into
DNA, therefore, inhibits DNA synthesis
- uses: pancreatic, lung and bladder cancer
- toxicity: myelosuppression, haemolytic-
uremic syndrome
 Anti-metabolites…
4. Ribonucleotide reductase inhibitor
Hydroxyurea
- Inhibits conversion of ribonucleotides to
deoxyribonucleotides, therefore, inhibits DNA
replication
- Uses: chronic myeloid leukaemia, ovarian
carcinoma, melanoma
- Toxicity: myelosuppression, renal impairment,
neurotoxic, stomatitis, nauesa and vomiting
 Mitotic inhibitors

1. Vinca alkaloids
-MoA: arrest mitosis by inhibiting
polymerization of microtubules
a) Vincristine
- uses: lymphomas and acute leukaemias
- toxicity: peripheral neuropathy, alopecia,
irritant to tissue
 Mitotic inhibitors…

b) Vinblasine
- uses: lymphomas, leukaemias, breast cancer,
testicular cancer, Euring’s sarcoma, kaposis
sarcoma
- toxicity: peripheral neuropathy, alopecia,
myelosuppression, local tissue injury
c) Vinorelbine
- uses: lung and breast cancer
- toxicity: peripheral neuropathy,
myelosuppression
 Mitotic inhibitors…
2. Taxanes
- MoA: promote assembly of microtubules- the
overly stable microtubules formed are
dysfunctional, thereby causing the death of the
cell
Paclitaxel (taxol)
- uses: breast, lung, ovarian, head and neck, and
bladder cancer
- Toxicty: myelosuppression, alopecia, arthralgia,
neuropathy
DNA cross-linking drugs and alkylating
agents
• MoA: form adducts with DNA causing DNA strand
breaks
a) Nitrogen mustard, chlorambucil, cyclophosphamide,
nelphalan, ifosfamide
- Alkylating agents –transfer an alkyl group to DNA
- uses: Hodgkins disease, lymphomas, small cell lung
cancer, breast and testicular cancer, chronic
lymphocytic leukemia, multiple myeloma, malignant
gliomas
- Toxicity: alopecia, leukemogenic, aspermia,
permanent sterility, hemorrhagic cystitis ( with
cyclophophamide and ifosfamide)
DNA cross-linking drugs and alkylating
agents….
b) Procarbazine
- Causes chromosomal damage and suppress
synthesis of DNA and RNA
- uses: hodgkin’s disease
- Toxicity: myelosuppression, nausea and
vomiting, neurotoxic, secondary leukaemias
 Topo-isomerase inhibitors

a) Anthracyclines
- MoA: inhibit topo-isomerase II and cause DNA strand
breaks through intercalation with DNA
1) Doxorubicin
- uses: acute leukemia, lymphoma, breast and lung
cancer
- toxicity: nausea/vomiting, myelosuppression,
alopecia, cardiotoxicity
2) Daunorubicin
- use: acute leukemias
- toxicity: as doxorubicin
 Topo-isomerase inhibitors…
b) Podophyllotoxins
Etoposide
- MoA: inhibit topo-isomerase II and cause DNA
strand breaks
- uses: lymphomas, testicular cancer, lung
cancer (especially small cell) acute leukemia
- toxicity: nausea vomiting, myelosuppression,
neutropenia, peripheral neuropathy
 Topo-isomerase inhibitors…
c) Camptothecins
Topotecan
- Inhibits topo-isomerase I and II resulting in
DNA damage
- uses: ovarian and small cell lung cancer
- toxicity: myelosuppression
 Platinum complexes
- MoA: establish cross-links within and between DNA
strands and inhibit DNA synthesis and function
a) Cisplatin
- uses: lung cancer, testcular, breast and ovarian cancer
- toxicity: severe persistent vomiting, nephrotoxic,
decrease Mg++, decrease Ca++, ototoxic, neurotoxic,
anaemia, myelosuppression
b) Carboplastin
- uses: lung, head and neck, ovarian and breast cancer
- toxicity: myelosuppression, peripheral neuropathy.
 Hormones

a) Tamoxifen
- MoA: oestrogen receptor antagonist
- Uses: oestrogen dependent breast cancer
- Toxicity: hot flushes, hypercalcaemia, deep venous
thrombosis
b) Diethylstibestrol
- An oestrogen- inhibits the growth of prostatic tissue by
blocking the production of luteinizing hormone thereby
decreasing synthesis of androgens
- Use: prostate cancer
- Adverse effects: gynaecomastia, impotence, thrombo-
embolism
 Hormones…
c) Flutamide
- Androgen receptor blocker
- use: prostate cancer
- adverse effects: decrease libido, hot flushes,
gynaecomastia
d) Leuprolide acetate
Inhibits gonadotropin secretion
- use: prostate cancer
- adverse effects: hot flushes, decreased libido
 Hormones…
e) Anastrozole
- Aromatase inhibitor: blocks conversion of
androgen to oestrogen
- breast cancer
- adverse effects: osteoporosis, hot flushes
f) Megestrol acetate
- Progestrone agonist
- breast and endometrial cancer
- adverse effects: weight gain, fluid retention
 Hormones…
g) Prednisolone
- Toxic to lymhoid tissue
- use: acute lymphocytic leukemia, lymphomas
- adverse effects: fluid retention, hypertension,
diabetes, increased susceptibility to infection,
moon face
 Miscellaneous
a) nitrosoureas-carmustine and lomustine
- Alkylate DNA
- use: brain tumor, lymphoma (carmustine)
- toxicity: myelosuppression, pulmonary toxicity,
nephrotoxic
b) Imatinib
- Inhibits tyrosine kinase
- use: chronic myeloid leukaemia, GI stremal
tumors
- toxicity: leukopenia, hepatotoxic, oedema
 Miscellaneous…
c) Bleomycin
- Causes DNA strand breaks
- use: squamous cell carcinoma, lymphoma, testicular
cancer
- toxicity: anaphylaxis, chills and fever, pulmonary fibrosis
d) Mitomycin
- Alkylates DNA
- use: gastric adenocarcinoma; colon, breast and lung
cancer, transitional cell cancer of the bladder
- toxicity: local extravation causes tissue necrosis,
myelosuppression, fever, leukopaenia, throbocytopaenia,
alopecia, haemolytic- uremic syndrome
 Miscellaneous…
e) Interferon-alpha
- anti-proliferative effect
- use: hairy cell leukemia, chronic myeloid
leukemia, Kaposi's sarcoma(AIDS), renal cell
cancer, melanoma
- toxicity: fatigue, fever, myalgias, arthralgias,
myelosuppression, nephrotic syndrome (rare)
 Miscellaneous…
f) Asparaginase
- An enzyme that depletes asparagine, on which
leukemic cells depend (they have limited
capacity to make L-asparagine)
- use: acute lymphocytic leukemia
- Toxicity: acute anaphylaxis, hyperthermia,
pancreatitis, hyperglycemia,
hypofibrinogenemia, seizures, coma, liver
dysfunction
 Miscellaneous…
g) Rituximab (a monoclonal antibody)
- Binds to CD 20 on B-cells
- use: B-cell lymphoma
- toxicity: hypersensitivity reactions
h) Actinomycin-D (Dactinomycin)
- Intercalates with DNA thereby inhibiting RNA synthesis
- wilm’s tumor, rhbdomyosarcoma, Euring’s sarcoma,
kaposi’s sarcoma, choriocarcinoma
- Toxicity: corrosive to tissue, stomatitis,
nausea/vomiting, myelosuppression