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Anticancer drugs
Dr. S. Parasuraman
Faculty of
Pharmacy, AIMST.
Anticancer drugs
• The anticancer drug either kill cancer cells or modify
their growth.
• Discovery of anticancer agents started after 1940’s (when
nitrogen mustard was used)
• Most of the agents were discovered in 1950-1970.
• Cancer treatment:
– Chemotherapy
– Radiotherapy
– Immunotherapy
– Surgery
Cellular
Pathways to
Malignancy
Aim of the cancer therapy
– Cure or prolong remission
– Palliation
– Adjuvant chemotherapy
• Cure or prolong remission
• Primary treatment modality for
Acute leukemias (in children)

Choriocarcinoma

Wilm’s tumour (in children)

Hodgkin’s disease

Ewing’s sarcoma (in children)

Lymphosarcoma

Retinoblastoma (in children)

Burkitt’s lymphoma

Rhabdomyosarcoma (in children)

Testicular teratomas, Seminoma
Aim of the cancer therapy
• Palliation
– Life prolong by chemotherapy: Breast cancer, Ovarian
carcinoma, myeloma, prostatic carcinoma, chronic
lymphatic leukemia, chronic myeloid leukemas, nonHodgkin lymphomas, head and neck cancer and lung
(small cells) cancer
– Life prolong by chemotherapy: Colorectal carcinoma,
carcinoma pancreas, carcinoma stomach, carcinoma
esophagus, renal carcinoma, malignant melanomas,
bronchogenic carcinoma (non small cells), hepatoma and
sarcoma.
Aim of the cancer therapy
• Adjuvant chemotherapy:
– Drugs used to clear residual malignant cells
(micrometastases) after surgery / radiotherapy. Adjuvant
chemotherapy may achieve apparent cure (especially in
early breast, lung and colonic cancer)
Therapeutic effect of anticancer agent
• Cancer arise form a single malignant cell, the therapeutic goal
of cancer chemotherapy may require “total tumour cell kill”
• Achievement of a therapeutic effect by combination therapy.
• Therapeutic effect achieved by killing actively “growing
tumour cells”.
• Anticancer agents should act only at “specific stages in the cell
cycle” (the S phase and M phase).
Classification of anticancer agents
• Major class of drugs
A. Cytotoxic drugs
B. Targeted drugs
C. Hormonal drugs
Classification of anticancer agents
Cytotoxic drugs
1. Alkylating agents
2. Platinum coordination: Cisplatin, Carboplatin, Oxaliplatin

3. Antimetabolites
4. Microtubule damaging agents: Vincristine, Vinblastine,
Vinorelbine, Paclitaxel, Docetaxel
5. Topoisomerase-2 inhibitor: Etoposide
6. Topoisomerase-1 inhibitor: Topotecan, Irinotecan
7. Antibiotics: Actinomycin D, Doxorubicin, Daunorubicin,
Epirubicin, Bleomycins, Mitomycin C.
8. Miscellaneous: Hydroxyurea, L-Asparaginase, Tretinoin,
Arsenic trioxide
Classification of anticancer agents
Targeted drugs
1.
2.
3.
4.
5.

Tyrosine proteinkinase inhibitors: Imatinib, Nilotinib
EGF receptor inhibitor: Gefitinib, Erlotinib
Angiogenesis inhibitors: Bevacizumab
Proteasome inhibitor: Bortezomib
Unarmed monoclonal antibody: Rituximab, Trastuzumab
Classification of anticancer agents
Hormonal drugs
1.
2.
3.
4.
5.
6.
7.
8.
9.

Glucocorticods: Prednisolone
Estrogens: Fosfestrol, ethinylestradiol
Selective estrogen receptor modulators: Tamoxifen
Selective estrogen receptor down-regulators: Fulvestrant
Aromatase inhibitors: Letrozole, Anastrozole
Antiandrogen: Flutamide
5-α reductase inhibitor: Finasteride
GnRH analogues: Nafarelin, Triotorelin
Progestins: Hydroxyprogesterone acetate
General Principles in chemotherapy of
cancer
•

Single clonogenic malignant cell is capable of producing progeny

that kill the host. To effective cure, all malignant cells must be
killed.
•

The proliferation rate of cancer cell is differ from normal cell.

The cytotoxic drugs kill cancer cell by first order kinetics.
•

‘Combined modality approach’ can be used for cancer therapy.

•

Poly pharmacy can be used for achieve ‘total tumour cell kill’.
General Principles in chemotherapy of
cancer
• Cytotoxic drugs are either cell cycle nonspecific (CCNS)
or cell cycle specific (CCS)
– cell cycle nonspecific kill resting as well as dividing
cells. E.g.: Mustine, cyclophoshamide, chlorambucil,
carmustine, cisplatin, L-asparginase.
General Principles in chemotherapy of
cancer

– cell cycle specific kill only actively dividing cells.
• G1: Vinblastine
• S: Mtx, cytarabine, fludarabine, G-TG, 6-MP, 5-FU, hydroxyurea,
mitomycin C, doxorubicin, daunorubicin
• G2: Daunorubicin, bleomycin, etoposide, topotecan
• M: Vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel
6-Mercaptopurine
6-Thioguanine
Methotrexate

Summary of MOA and site of action of chemotherapeutic agents
Purines and pyrimidines

Inhibit purine ring synthesis

Ribonucleotides
Hydroxyurea

Inhibit ribonucleotide reductase

Inhibit dTMP synthesis

Methotrexate
5-Fluorouracil

Deoxyribonucleotides

Cytarabine
Bleomycin

Doxorubicin
Daunorubicin
Dactinomycin

DNA
Scission of DNA
Intercalate DNA

Alkylating agents
Nitrosoureas
Cisplatin
L-Asparaginase
Vinca alkaloids
Paclitaxel
Colchicine

Inhibit DNA synthesis

Cross-link DNA
RNA
Inhibit protein synthesis

Proteins
Inhibit microtubule function

Protein tyrosin kinase inhibitor

microtubules

Block activity

Enzymes
General toxicity of cytotoxic
drugs
• Cytotoxic drugs have more profound effect on rapidly
multiplying cells, because its targeting action in nucleic acid
and there precursors.
• Bone marrow: Depression of bone marrow results in
granulocytopenia,
agranulocytosis,
thrombocytopenia,
aplastic anaemia.
• Lymphoreticular tissue: Lymphocytopenia and inhibition of
lymphocyte function results in suppression of cell mediated as
well as humoral immunity.
• Oral cavity: Stomatitis, neutropenia, thrombocytopenia
• GIT: Diarrhoea, shedding of mucosa, haemorrhages, Nausea
and vomiting
• Skin: Alopecia (due to damage of cells in hair follicles)
• Gonads: Oligozoospermia in males; amenorrhoea in females.
• Foetus: Cytotoxic agents causes abortion, foetal
death, teratogenesis in pregnant women.
• Carcinogenicity:
Secondary
cancers,
especially
leukaemias, lymphomas and histocytic tumours appear with
greater frequency many years after the use of cytotoxic drugs.
• Hyperuricaemia
• Individual drugs may produce specific adverse effects,
e.g.
neuropathy by vincristine,
Cardiomyopathy by doxorubicin,
cystitis and alopecia by cyclophosphamide.
Thank you

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Anticancer drugs 1 introduction and classification

  • 1. Anticancer drugs Dr. S. Parasuraman Faculty of Pharmacy, AIMST.
  • 2. Anticancer drugs • The anticancer drug either kill cancer cells or modify their growth. • Discovery of anticancer agents started after 1940’s (when nitrogen mustard was used) • Most of the agents were discovered in 1950-1970. • Cancer treatment: – Chemotherapy – Radiotherapy – Immunotherapy – Surgery
  • 4. Aim of the cancer therapy – Cure or prolong remission – Palliation – Adjuvant chemotherapy • Cure or prolong remission • Primary treatment modality for Acute leukemias (in children) Choriocarcinoma Wilm’s tumour (in children) Hodgkin’s disease Ewing’s sarcoma (in children) Lymphosarcoma Retinoblastoma (in children) Burkitt’s lymphoma Rhabdomyosarcoma (in children) Testicular teratomas, Seminoma
  • 5. Aim of the cancer therapy • Palliation – Life prolong by chemotherapy: Breast cancer, Ovarian carcinoma, myeloma, prostatic carcinoma, chronic lymphatic leukemia, chronic myeloid leukemas, nonHodgkin lymphomas, head and neck cancer and lung (small cells) cancer – Life prolong by chemotherapy: Colorectal carcinoma, carcinoma pancreas, carcinoma stomach, carcinoma esophagus, renal carcinoma, malignant melanomas, bronchogenic carcinoma (non small cells), hepatoma and sarcoma.
  • 6. Aim of the cancer therapy • Adjuvant chemotherapy: – Drugs used to clear residual malignant cells (micrometastases) after surgery / radiotherapy. Adjuvant chemotherapy may achieve apparent cure (especially in early breast, lung and colonic cancer)
  • 7. Therapeutic effect of anticancer agent • Cancer arise form a single malignant cell, the therapeutic goal of cancer chemotherapy may require “total tumour cell kill” • Achievement of a therapeutic effect by combination therapy. • Therapeutic effect achieved by killing actively “growing tumour cells”. • Anticancer agents should act only at “specific stages in the cell cycle” (the S phase and M phase).
  • 8. Classification of anticancer agents • Major class of drugs A. Cytotoxic drugs B. Targeted drugs C. Hormonal drugs
  • 9. Classification of anticancer agents Cytotoxic drugs 1. Alkylating agents 2. Platinum coordination: Cisplatin, Carboplatin, Oxaliplatin 3. Antimetabolites 4. Microtubule damaging agents: Vincristine, Vinblastine, Vinorelbine, Paclitaxel, Docetaxel 5. Topoisomerase-2 inhibitor: Etoposide 6. Topoisomerase-1 inhibitor: Topotecan, Irinotecan 7. Antibiotics: Actinomycin D, Doxorubicin, Daunorubicin, Epirubicin, Bleomycins, Mitomycin C. 8. Miscellaneous: Hydroxyurea, L-Asparaginase, Tretinoin, Arsenic trioxide
  • 10. Classification of anticancer agents Targeted drugs 1. 2. 3. 4. 5. Tyrosine proteinkinase inhibitors: Imatinib, Nilotinib EGF receptor inhibitor: Gefitinib, Erlotinib Angiogenesis inhibitors: Bevacizumab Proteasome inhibitor: Bortezomib Unarmed monoclonal antibody: Rituximab, Trastuzumab
  • 11. Classification of anticancer agents Hormonal drugs 1. 2. 3. 4. 5. 6. 7. 8. 9. Glucocorticods: Prednisolone Estrogens: Fosfestrol, ethinylestradiol Selective estrogen receptor modulators: Tamoxifen Selective estrogen receptor down-regulators: Fulvestrant Aromatase inhibitors: Letrozole, Anastrozole Antiandrogen: Flutamide 5-α reductase inhibitor: Finasteride GnRH analogues: Nafarelin, Triotorelin Progestins: Hydroxyprogesterone acetate
  • 12. General Principles in chemotherapy of cancer • Single clonogenic malignant cell is capable of producing progeny that kill the host. To effective cure, all malignant cells must be killed. • The proliferation rate of cancer cell is differ from normal cell. The cytotoxic drugs kill cancer cell by first order kinetics. • ‘Combined modality approach’ can be used for cancer therapy. • Poly pharmacy can be used for achieve ‘total tumour cell kill’.
  • 13. General Principles in chemotherapy of cancer • Cytotoxic drugs are either cell cycle nonspecific (CCNS) or cell cycle specific (CCS) – cell cycle nonspecific kill resting as well as dividing cells. E.g.: Mustine, cyclophoshamide, chlorambucil, carmustine, cisplatin, L-asparginase.
  • 14. General Principles in chemotherapy of cancer – cell cycle specific kill only actively dividing cells. • G1: Vinblastine • S: Mtx, cytarabine, fludarabine, G-TG, 6-MP, 5-FU, hydroxyurea, mitomycin C, doxorubicin, daunorubicin • G2: Daunorubicin, bleomycin, etoposide, topotecan • M: Vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel
  • 15. 6-Mercaptopurine 6-Thioguanine Methotrexate Summary of MOA and site of action of chemotherapeutic agents Purines and pyrimidines Inhibit purine ring synthesis Ribonucleotides Hydroxyurea Inhibit ribonucleotide reductase Inhibit dTMP synthesis Methotrexate 5-Fluorouracil Deoxyribonucleotides Cytarabine Bleomycin Doxorubicin Daunorubicin Dactinomycin DNA Scission of DNA Intercalate DNA Alkylating agents Nitrosoureas Cisplatin L-Asparaginase Vinca alkaloids Paclitaxel Colchicine Inhibit DNA synthesis Cross-link DNA RNA Inhibit protein synthesis Proteins Inhibit microtubule function Protein tyrosin kinase inhibitor microtubules Block activity Enzymes
  • 16. General toxicity of cytotoxic drugs
  • 17. • Cytotoxic drugs have more profound effect on rapidly multiplying cells, because its targeting action in nucleic acid and there precursors. • Bone marrow: Depression of bone marrow results in granulocytopenia, agranulocytosis, thrombocytopenia, aplastic anaemia. • Lymphoreticular tissue: Lymphocytopenia and inhibition of lymphocyte function results in suppression of cell mediated as well as humoral immunity. • Oral cavity: Stomatitis, neutropenia, thrombocytopenia • GIT: Diarrhoea, shedding of mucosa, haemorrhages, Nausea and vomiting • Skin: Alopecia (due to damage of cells in hair follicles) • Gonads: Oligozoospermia in males; amenorrhoea in females.
  • 18. • Foetus: Cytotoxic agents causes abortion, foetal death, teratogenesis in pregnant women. • Carcinogenicity: Secondary cancers, especially leukaemias, lymphomas and histocytic tumours appear with greater frequency many years after the use of cytotoxic drugs. • Hyperuricaemia • Individual drugs may produce specific adverse effects, e.g. neuropathy by vincristine, Cardiomyopathy by doxorubicin, cystitis and alopecia by cyclophosphamide.