Cancer Chemotherapy

Neoplasia : New growth

uncontrolled proliferation / multiplication of cells

Cancer Characteristics :
growth not subjected to normal restriction of that tissue defective differentiation

local invasiveness
metastasis
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Different approaches to treat Cancer

Surgery Radiotherapy

Chemotherapy
Endocrinal therapy Immunotherapy- immunostimulants can be helpful in eradicating residual cancer cells after chemotherapy

Novel approaches for Cancer chemotherapy

Manipulation of immune system
STIMULATE IMMUNITY AGAINST PARTICULAR CELLS

Induction of differentiation
CANCER CELLS LOSE DIFFERENTIATION

Anti-angiogenesis: cutting off blood supply

CA CELLS HAVE THEIR OWN COLLATERAL BLOOD SUPPLY

Gene Therapy (UPCOMING FIELD) Biologic response modifiers

Principles of cancer chemotherapy

Log-kill hypothesis
Cytotoxic actions of anti-cancer drugs follow firstorder kinetics
Means cytotoxic drugs kill constant fraction (not a fixed number of cells) (log kill effect) of cells (rationale for drug combination) Drugs are relatively selectively toxic to the cancer cells Cytotoxicity is proportional to total drug exposure
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Principles of cancer chemotherapy

Growth fraction
Cytotoxic drugs are more effective against tumors that have a high growth fraction (large percentage actively dividing)
Normal cells with high growth fraction (e.g., bone marrow, GI cells, hair follicles) are also more sensitive to anticancer drugs

Main mechanisms of Anti-cancer drugs

Damage the DNA of the affected cancer cells apoptosis Inhibit the synthesis of new DNA inhibition of incorporation of purine or pyramidine nucleotides
Inhibit mitosis, CAUSE METAPHASE ARREST

Anti-Cancer Drugs

Different Groups of anti-cancer Drugs: Alkylating agents Antimetabolites Microtubule inhibitors Topoisomerase Inhibitors Cytotoxic Antibiotics Hormones Monoclonal antibodies
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Mechanisms of anti-cancer drugs

**** ACT BY INIHBITING MITOSIS SO MORE ACTIVE IN THE M PHASE.

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Cell cycle**
All cells (normal and cancer cells) go through growth cycle which can be divided into 4 cycling phases named, G1, S, G2 and M. Cells which are in the resting phase are said to be in phase G0 DNA synthesis takes place in S Phase.

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Cell Cycle

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**Cell cycle specific drugs (CCS)

Cell cycle specific anticancer drugs act on tumor stem cells only when they are traversing the cell cycle (replicating cells) e.g., Anti-metabolites (METHOTREXATE) Vinca alkaloids (VINCRISTINE) Taxanes Bleomycin
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**Cell cycle non-specific drugs (CCNS)

Cell cycle non-specific anticancer drugs act on dividing as well as resting tumor cells. However, they exhibit most activity in rapidly replicating cells e.g., Alkylating agents Platinum analogs Antibiotics
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Mechanisms of drug resistance

Abnormal transport
P-glycoprotein dependent efflux, THROWS OUT ALL DRUGS THAT ENTERS CANCER CELLS

Increased cellular inactivation Enhanced DNA repair Altered target protein Decreased cellular retention

Chances of resistance can be decreased by short term but intensive intermittent therapy with combination of different drugs
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Benefits of combination chemotherapy

Increases maximum cell kill and decreases toxicity
Kills cells in tumors with heterogeneous cell populations Reduces the chances of development of resistant clones***
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Side effects of cancer chemotherapy

Cytotoxic effects result mainly from inhibition of cell replication in tissues which have a high cell turnover rate Bone marrow Gastrointestinal epithelium Hair follicle Gametogenesis in gonads (INFERTILITY)
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Toxicity of cancer chemotherapy Bone marrow***

Myelosuppression: results in granulocytopenia, lymphocytopenia, thrombocytopenia and anemia Mucositis, Diarrhea, bleeding, Emesis (Cisplatin) Alopecia Infertility Leukemia (alkylating agents) -it creates an onocogenic gene and cause leukemia Opportunistic infections
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Gastrointestinal epithelium (MOUTH TO ANUS) Hair follicle Gametogenesis in gonads Secondary malignancies -drug can acutally create cancer!
Infections

Tumor lysis syndrome

Increased uric acid production Gout

***Role of Allopurinol
Doses of chemotherapeutic agents which are metabolized by Xanthine oxidase (eg, 6Mercaptopurine) should be decreased while giving Allopurinol
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Anti-cancer drugs

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Anti-Cancer Drugs
Different Groups of Anti-cancer Drugs:
Alkylating agents Antimetabolites Microtubule inhibitors Topoisomerase inhibitors Cytotoxic Antibiotics Hormones Monoclonal antibodies
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Alkylating agents

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Alkylating agents: They are Cell cycle non-specific drugs (CCNS)

Nitrosoureas Others (for brain tumors) Cyclophosphamide Carmustine Busulfan Mechlorethamine Lomustine Cisplatin Chlorambucil Procarbazine Melphalan Dacarbazine
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**Nitrogen mustards

ALKYLATING AGENTS
Mechanism of action
They undergo intramolecular cyclization to form either an ethyleneimonium or a carbonium ion which are strongly electrophilic
These intermediates can alkylate (transfer of alkyl groups) various cellular constituents by formation of covalent bonds with nucleophile groups***
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ALKYLATING AGENTS
Mechanism of action The position N7 of guanine residues in DNA is susceptible Alkylation results in cross linking /

abnormal base pairing / scission of DNA strand.

Alkylation of guanine of a single strand of the DNA molecule results in miscoding.
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ALKYLATING AGENTS :
Mechanism of action

Alkylation of guanine of both strands of the DNA molecule results in cross-linking ---Cytotoxic action. CAUSES DNA DAMAGE!!

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ALKYLATING AGENTS :
Directly damage the DNA
***Active against proliferating and nonproliferating cells (CCNS); however, proliferating cells are more sensitive to the drug, Dose limiting Myelosuppression ***Genotoxic and increase risk of leukemia
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Alkylating agents: Resistance

Resistance occurs due to
decreased permeability of the drug
increased conjugation with thiols such as glutathione , and increased DNA repair

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Mechlorethamine
Administration: given IV because of its vesicant activity (blistering agent) Extravasation may cause tissue necrosis and sloughing **Clinical uses : Hodgkins disease (MOPP regimen)
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- Cyclophisphamide: most commonly used

alkylating agent

Cyclophosphamide / Ifosfamide

Mode of action:

***It is a prodrug - convert to the active metabolite by hepatic mixed function oxidase

Pharmacokinetics: - preferred orally - does not have vesicant effects - cytotoxic metabolite is acrolein
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Cyclophosphamide / Ifosfamide
Toxicity : - causes hemorrhagic cystitis*** (due to
acrolein)

This can be decreased by adequate hydration as well as by the use of MESNA*** (2- mercaptoethane sulfonate) Ifosfamide has a less potential to cause hemorrhagic cystitis
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 Clinical uses : Cancer of breast, Ovary, CLL and NonHodgkins lymphoma (CHOP regimen) As Immunosuppressant in autoimmune conditions (e.g. SLE)

Cyclophosphamide / Ifosfamide

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Melphalan
Can be given orally ***Therapeutic Use: multiple myeloma ***Side effects: Bone marrow suppression, Pancreatitis

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Chlorambucil
***Therapeutic Uses: CLL - Chronic Lymphocytic Leukemia (agent of choice)
Produces less severe BMS than other nitrogen mustards
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Nitrosoureas
***Carmustine & Lomustine :
highly lipophilic; easily enter the brain, SO PRIMARILY USED FOR BRAIN TUMORS - LIMITED USE IN THE TREATMENT OF OTHER CANCERS.

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Nitrosoureas
Carmustine : Toxicity : Aplastic anemia on prolonged use, hepatitis (carmustine) **Clinical uses : Brain tumors*** R/A: Carmustine (IV) Lomustine (Oral)

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Busulfan
selectively depresses granulocytopoiesis
Clinical uses : Chronic Myeloid Leukemia (CML) Adverse effects : Pulmonary fibrosis*** (busulfan lung) Myelosuppression
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Procarbazine, Dacarbazine
They are converted to active intermediates that can alkylate DNA. Clinical uses : Hodgkins disease CURRENT REGIMEN: ***ABVD (Adriamycin=Doxobubicin, Bleomycin, Vinblastine, Dacarbazine ) MOPP (Procarbazine) old regimen Malignant Melanoma

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Procarbazine, Dacarbazine
Adv effects: - Nausea, vomiting - Myelosuppression (mild)

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Temozolamide
Related to Dacarbazine Differences are: Temezolamide can cross BBB, but Dacarbazine can not Temezolamide given orally, whereas Dacarbazine IV

approved recently for brain tumors (treatmentresistant gliomas, anaplastic astrocytomas)

also has the property of inhibiting the repair enzyme
therefore less chance of resistance

Adv effects: Nausea and vomiting, myelosuppression

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Cisplatin
a small platinum coordination complex

Mechanism of Action
- inhibits DNA synthesis by formation of both, interstrand and intrastrand** cross-links (adjacent guanines are most frequently crosslinked)

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Cisplatin
***Adverse effects : *Nephrotoxicity (ameliorated by hydration and diuresis) (antidote: amifostine) Strong emetic effect (use Ondansetron) Neurotoxicity (deafness)

***Therapeutic Uses : testis, ovary, bladder and lung cancer

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Carboplatin
Similar but less severe toxicities than cisplatin Also causes myelosuppression (doselimiting)

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Anti-metabolites
Folate analogs Purine analogs Pyrimidine analogs
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Antimetabolites: They are cell cycle specific (CCS) agents. They are structural analogs of essential cellular metabolites (folic acid, purine & pyrimidine bases) and competitively inhibit the essential enzymes involved in DNA synthesis. Folate Purine analogs Pyrimidine analogs analogs and others

Methotrexate

6- Mercaptopurine 6- Thioguanine Fludarabine Cladribine

5-Fluorouracil Cytarabine Gemcitabine 51 Capecitabine

Anti-metabolites
Mechanism of action They are structural analogues of folic acid / purine / pyrimidine bases found in DNA act as anti-metabolites to inhibit enzymes required for DNA synthesis.

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Anti-metabolites
Mimic cellular essential metabolites **Active against proliferating cells * (S phase specific) Myelosuppression is the dose-limiting toxicity for all drugs in this class.
Teratogenic but not leukemogenic ***(not genotoxic)
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Anti-metabolites
All are CCS agents.
All need to be activated before they can act Some are used as immunosuppressants: - in autoimmune diseases, organ transplantation
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Folate analogs
Methotrexate

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Methotrexate
structurally related to folic acid

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Methotrexate
Mode of action :
inhibits dihydrofolate reductase leading to inhibition of tetrahydrofolate (THF) synthesis Deficiency of THF causes inhibition of onecarbon transfer reactions required for the synthesis of deoxynucleotides & ribonucleotides; leading to depressed DNA, RNA, and protein synthesis and ultimately cell death.
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***Methylene- tetrahydrofoate is required for:

Purine synthesis (for RNA & DNA synthesis) Conversion of dUMP to dTMP (for DNA synthesis) Synthesis of methionine, serine

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Methotrexate
- can be given Orally, IV, IM and Intrathecally. - does not enter the brain (has to be given intrathecally to get to CNS) Therapeutic Uses : ALL, Choriocarcinoma***, Burkitts lymphoma in children, breast cancer Rheumatoid arthritis, Psoriasis
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Methotrexate
Toxicity : Most common: Bone marrow suppression (BMS) Mucositis, Stomatitis Alopecia

Leucovorin rescue: BMS can be reduced by administration of folinic acid (Leucovorin / N5 formyl THF / Citrovorum factor) which by-pass the dihydrofolate reductase step in tetrahydrofolate synthesis. This agent can rescue host cells but not cancer cells.
Dose of leucovorin must be kept minimal to avoid possible interference with the antitumor action of MTX
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Methotrexate
Toxicity : Renal damage (Crystalluria): Alkalinization of the urine and hydration prevent this problem

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Purine analogs
6-Mercaptopurine 6-Thioguanine Fludarabine Cladribine
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Purine analogs
6-Mercaptopurine and 6-Thioguanine
***Mercaptopurine, analog of adenine, inhibits the biosynthesis of purine nucleotides.

***Thioguanine is an anti-metabolite in the synthesis of guanine nucleotides.

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Purine analogs
Purine analogs : Anti-metabolites M/A 6-Mercaptopurine and 6-Thioguanine are metabolized by hypoxanthine-guanine phosphoribosyltransferase*** (HGPRT) to toxic nucleotides, thio-IMP and then to thio-GMP. thio-IMP and thio-GMP inhibit enzymes involved in purine nucleotide interconversion
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Purine analogs
Purine analogs : Anti-metabolites M/A Thio-GMP, after phosphorylation to diand triphosphates can be incorporated into DNA, resulting in non-functional RNA and DNA synthesis

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Resistance: 6 MP
Generally due to deficiency in tumor cells of HGPRT (for example, in LeschNyhan Syndrome, in which patients lack this enzyme) Increased dephosphorylation (thio-IMP is phosphorylated to work as inhibitor), or Increased metabolism of the drug to thiouric acid or other metabolites
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Purine analogs
6-Mercaptopurine: ***6-MP is metabolized by xanthine oxidase to inactive metabolites. ***Simultaneous therapy with Allopurinol and 6-MP results in excessive toxicity unless the dose of 6-MP is reduced to 25% (***Not with 6-TG because as it is not metabolized by xanthine oxidase. 6-TG is metabolized by Smethylation).
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Purine analogs

Clinical uses of Purine analogs : 6-Mercaptopurine : ALL 6-Thioguanine : AML

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Purine analogs
Fludarabine (Fluoro-adenine arabinoside ) Interferes with DNA synthesis and induces cellular apoptosis ***Used in CLL and non-Hodgkins lymphoma Given IV Main adverse effect: myelosuppression

Cladribine (Chlordeoxyadenosine) ***Used in hairy cell leukemia and CLL

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Pyrimidine analog
5-Fluorouracil

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Pyrimidine analog
5-Fluorouracil:
a thymidine antimetabolite. 5-Fluorouracil is converted into FdUMP which inhibits thymidylate synthase and leads to thymine less death of cell. So no DNA synthesis, because thymine is required for synthesis.

The failure to synthesize the thymidine nucleotide results in little or no production of DNA.
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Pyrimidine analog
5- FU
administered IV or topically ***Leucovorin is administered with 5-FU to enhance its effect. (by allowing thymidylate synthase to work) ***Uses : Breast, colorectal, ovarian, pancreatic and gastric carcinomas ***Basal cell carcinoma of skin (topically). 81

Pyrimidine analog
5- FU: Adverse effects
GI symptoms: Nausea, vomiting, diarrhea, severe ulceration of oral and GI mucosa BMS

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Other anti-metabolites
Cytarabine (Cytosine arabinoside ara C) is phosphorylated to ara CTP that inhibits DNA polymerase and also causes DNA strand breakage.

***Cytarabine use is limited to AML *.

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Other anti-metabolites
Gemcitabine : Inhibits DNA synthesis via chain termination Uses
***adenocarcinoma of pancreas non-small cell lung cancer and bladder carcinoma.

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Other anti-metabolites
Capecitabine : Converted to 5-FU Inhibits thymidylate synthetase

***Used for:
metastatic breast * and metastatic colorectal cancer
Common adverse effects: Dermatitis and myelosuppression
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Anti-mitotic Drugs
Vinca alkaloids Taxanes

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Antimitotic Drugs (CCS drugs) Vinca alkaloids They Inhibit tubulin polymerization Taxanes They promote assembly of microtubules (tubulin polymerization) & prevent microtubule disassembly (PROMOTE ASSEMBLY) Paclitaxel Docetaxel
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Vincristine Vinblastine

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Antimitotic Drugs
All are CCS agents. All act on the ***M phase of the cell cycle.

Mechanism of action They inhibit Mitotic spindle formation that is essential for equal partitioning of DNA into two daughter cells.

metaphase arrest
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Antimitotic Drugs
Drug toxicity: Cytotoxic effects mainly on bone marrow, gastrointestinal epithelium and the hair follicle. Emetic effects due to stimulation of CTZ.

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Vinca alkaloids: Vincristine,

Vinblastine
Obtained from Periwinkle plants Mechanism of action : - they inhibit tubulin polymerization, prevent microtubule assembly and hence inhibit the formation of mitotic spindle - Resistance is often accounted for Pglycoprotein that transports drugs out of cells

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Vinca alkaloids: Vincristine,

Vinblastine ***Toxicity : Vincristine: peripheral neuropathy (neurotoxicity) and SIADH
Vinblastine causes myelosuppression.

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Vinca alkaloids:Uses
Vincristine : (aka ONCOVIN)
Hodgkins disease (MOPP regimen), NonHodgkins Lymphoma (CHOP regimen), ALL and Wilms tumor

Vinblastine :
Hodgkin's lymphoma (ABVD regimen) and testicular cancer (PVB regimen)
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Taxanes: Paclitaxel and Docetaxel

They prevent microtubule disassembly & promote tubulin polymerization

***Toxicity :
- Neutropenia is dose limiting. Treat NEUTROPENIA with G-CSF (Filgrastim). - Peripheral neuropathy - Hypersensitivity reactions (esp Paclitaxel): Premedicate the patients with Dexamethasone, Diphenhydramine and H2 blockers - Docetaxel contraindiacted in patients with heart diseases as it causes fluid retention 98

Taxanes: Paclitaxel and Docetaxel

Clinical uses : Advanced breast, lung and Ovarian cancer Resistance : - associated with expression of P-glycoprotein (efflux)

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Topoisomerase Inhibitors

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Topoisomerase Inhibitors Topoisomerase - I inhibitors Topoisomerase - II inhibitors

Topotecan Irinotecan

Etoposide (VP-16) Teniposide

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Topoisomerse inhibitors
Topotecan is a camptothecin analogue Etoposide is a podophyllin analogue. Mechanism of action DNA topoisomerases are enzymes that relieve the torsional strain caused by the unwinding of the DNA during the replication. Topoisomerase I breaks and reseals single- DNA strands, whereas topoisomerase II breaks and reseals both strands of DNA.
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Topoisomerse inhibitors
Topotecan inhibits topoisomerase I Etoposide inhibits topoisomerase II In this way, both prevent the resealing of nicked strands of DNA. The final result is accumulation of DNA breaks and cell death. They act mainly in the S and G2 phases of the cell cycle***
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Topoisomerse inhibitors
Etoposide and Topotecan Both can cross the blood brain barrier. Toxicity Myelosuppression and alopecia Uses Topotecan is used for metastatic ovarian cancer *, lung and colon cancer. ***Etoposide is used for testicular *, lymphoma and lung cancers Teniposide ALL
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