1. UNIVERSITY OF LUSAKA
CANCER CHEMOTHERAPY

2. 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

3. 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

4. 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

5. 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

6. 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)

7. 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,

8. 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

9. Classes of Anti-cancer drugs
Anti-metabolites
Mitotic inhibitors
DNA cross-linking drugs and alkylating agents
Topo-isomerase inhibitors
Platinum complexes
Hormones
Miscellaneous

10. Anti-metabolites 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

11. 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

12. Anti-metabolites… 2. Purine antagonist
6-mercaptopurine (a purine analogue)
Blocks de novo purine synthesis
uses: acute leukemia
Toxicity: mutagenic, myelosuppression, immunosuppression
b) Thioguanine (a purine analogue)
Uses: leukemias
Toxicity: myelosuppression, immunosuppression, hepatotoxic, nausea/vomiting, diarrhea

13. Anti-metabolites… 3. Pyrimidine antagonists 5-fluoro-uracil
Inhibits thymidylate synthetase, therefore, inhibits DNA synthesis
uses: GI tumor, breast cancer
toxicity: mucositis, alopecia, myelosuppression, diarrhoea, nausea and vomiting, neurotoxicity

14. 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,

15. 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

16. 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

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

18. 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

19. 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

20. DNA cross-linking drugs and alkylating agents
MoA: form adducts with DNA causing DNA strand breaks
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)

21. 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

22. Topo-isomerase inhibitors
Anthracyclines
MoA: inhibit topo-isomerase II and cause DNA strand breaks through intercalation with DNA
Doxorubicin
uses: acute leukemia, lymphoma, breast and lung cancer
toxicity: nausea/vomiting, myelosuppression, alopecia, cardiotoxicity
Daunorubicin
use: acute leukemias
toxicity: as doxorubicin

23. 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

24. 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

25. Platinum complexes
MoA: establish cross-links within and between DNA strands and inhibit DNA synthesis and function
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.

26. Hormones 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

27. Hormones… c) Flutamide Androgen receptor blocker use: prostate cancer
adverse effects: decrease libido, hot flushes, gynaecomastia
d) Leuprolide acetate
Inhibits gonadotropin secretion
adverse effects: hot flushes, decreased libido

28. 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

29. Hormones… g) Prednisolone Toxic to lymhoid tissue
use: acute lymphocytic leukemia, lymphomas
adverse effects: fluid retention, hypertension, diabetes, increased susceptibility to infection, moon face

30. Miscellaneous 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

31. 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

32. 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)

33. 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

34. 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