Chemotherapeutic Agents

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Actively dividing cells are at center of tumor

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Tumor killing by drugs follows
first order kinetics
(i.e. a fixed fraction of tumor cells are killed during chemotherapy = Log-kill hypothesis)

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4 phases of cell cycle:
1. G1: prep DNA synthesis
2. S: DNA replication
3. G2: proof read before division
4. M: cell division

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G1 phase of cell cycle involves (3)

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1. prep for DNA synthesis
2. synthesis of substrates: ribo & deoxyribonucleotides
3. synthesis of enzymes for DNA formation

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S phase of cell cycle involves

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DNA replication/Synthesis

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G2 phase of cell cycle involves

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1. proof reading [of new DNA]
2. correction of mismatches
3. protein synthesis

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M phase

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is the separation of Chromatides and division into 2 cells

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G0 Phase is the

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differentiation into mature cell

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chemo agents broad classification

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1-cell cycle specific drugs

2-cell cycle non-specific drugs

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cell cycle specific drugs

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These cancer chemotherapy drugs act in particular cell phase of cell cycle and are effective only against replicating cells

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cell cycle non-specific drugs

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These cancer chemotherapy drugs act at various phases of cell cycle and are effective on both replicating and resting cells (G0)

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3 principles of combination cancer chemotherapy

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1. achieve maximal killing
2. acceptable toxicity
(without causing lethal organ damage)
3. prevent resistance

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first principle of combination cancer therapy: achieve maximal killing

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Combining drugs known to be effective against tumor, ideally with different mechanism of action so that each kills a different fraction of tumor is the

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second principle of combination cancer therapy: acceptable toxicity without causing lethal organ damage

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Most anticancer cells kill both cancer cells and normal cells

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Acceptable toxicity of combination cancer therapy (2nd Principle) kills these normal cells (include effect)

((normal cells being affected by chemo agents ))

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1. Bone marrow: neutro- and thrombocytopenia
2. GI mucosa: mucositis & blisters
3. Hair Follicle: alopecia
4. Gonads: infertility

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Because most anticancer drugs induce DNA damage, they are considered

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carcinogenic

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most carcinogenic chemotherapeutic agents

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procarbazine,
melphalan,
cisplatin)

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Principle 2 of combination cancer therapy is based on the idea that the toxicity of any one drug is mostly

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confined to one particular organ
(thus, drugs with different toxicity profile should be combined)

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These 2 anticancer drugs' major toxicity is hemorrhagic cystitis

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1. Cyclophosphamide
2. Ifosfamide
(reduced by MESNA)

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MESNA

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1

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This anticancer drug's major toxicity is pulmonary fibrosis (LUNGS)

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Bleomycin

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Cisplatin major toxicity

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nephrotoxicity
deafness (KIDNEY & CNVIII)

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what to add to cisplatin to reduce their nephrotoxicity and ototoxicity

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Amifostine

hydration

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major side eefects of anthracyclins

1. Doxorubicin
2. Daunorubicin

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dilated cardiomayopathy

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how to reduce risk of dilated cardio in anthracyclin

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(reduce with Dexrazoxane)

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tetra D of anthracyclin

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D : Dilated cardiomyo
D : Doxurobicin
D : Dounorubicin
D : Dex-razoxane

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major side effect of Vincristine

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periphral neuropathy

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These 3 anticancer drugs' major toxicity is bone marrow suppression

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1. Etoposide
2. Methotrexate
3. Vinblastine

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how to decrease chemo toxicity on BM

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(reduce with Filgrastim (GM-CSF))
(MTX specific reduce with Leucovorin (THF))

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This anticancer drug's major toxicity is pancreatitis & bleeding

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L-asparagine

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A tumor cell has a mutation of dihydrofolate reductase enzyme develops

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resistance

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Multidrug resistance is mediated by

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p-glycoprotein
(efflux drug by ATP-dependent channel)

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Hodgkin's Lymphoma regimen

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ABVD regimen
1. A = Adriamycin
2. B = Bleomycin
3. V = Vincristine
4. D = Dacarbazine

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ABVD cell cycle effect

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Various Stages of Cell Cycle
1. Adriamycin at G0
2. Bleomycin at G2
3. Vincristine at M
4. Dacarbazine at G0

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ABVD regimen toxicity

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Toxicity at Various Organs
1. Adriamycin: Caridotoxicity
2. Bleomycine: Pulmonary Fibrosis
3. Vincristine: neurotoxicty
4. Dacarbazine: bone marrow

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testicular cancer regimen

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BEP regimen
1. Bleomycin: G2
2. Etoposide: Late S & G2
3. CisPplatin: cell cycle nonspecific

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BEP regimen toxicity

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1. Bleomycin: pulmonary fibrosis
2. Etoposide: Bone marrow toxic
3. Cisplatin: nephro & ototoxicity

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Adjuvant Chemotherapy

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Chemotherapy that is added in addition to surgery or radiotherapy

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Neo-adjuvant chemotherapy

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Chemotherapy that is given before surgery to decrease the size of the tumor

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Induction chemotherapy

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Chemotherapy that is given to obtain complete remission from the tumor, usually blood cancers

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Maintenance chemotherapy

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Chemotherapy that is given to maintain remission from the cancer

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classification of chemotherapeutics

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Alklating agents
Antimetabolites
Natural products
Antitumor antibiotics
Hormonal agents
Miscellaneous agents
signal transduction inhibitors

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Alklating agents

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1. Cyclophosphamide
2. Cisplatin
3. Melphalan

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Antimetabolites

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1. MTX
2. 5-FU
3. Gemcitabine

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Natural products

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1. Etoposide
2. Paclitaxel
3. Vincristine

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Antitumor antibiotics

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1. Bleomycin
2. Doxorubicin
3. Daunorubicin

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Hormonal agents

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1. Glucocorticoids
2. Estrogens
3. Progestins
4. Anti-androgens

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Miscellaneous agents

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. Arsenic trioxide
2. Hydroxyurea
3. L-asparaginase

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signal transduction inhibitors

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1. Imantinib
2. Gefitinib

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oral chemo for HCC

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sorafaneb