CANCER CHEMOTHERAPY (1)

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CANCER CHEMOTHERAPY
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Introduction

• Cancer is a group of diseases in which there is
  uncontrolled multiplication and spread within the
  body of abnormal forms of the body's own cells,
  OR
• A group of diseases that occur when malignant
  forms of abnormal cell growth develop in one or
  more body organs.
• These cancer cells continue to divide to produce
  tumors

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Tumors can be benign or malignant
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• Both benign and malignant tumours manifest
  uncontrolled proliferation.
• The appearance of these abnormal characteristics
  reflects altered patterns of gene expression in
  the cancer cells, resulting from genetic
  mutations.

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The pathogenesis of cancer.
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Cont

• Cancer cells manifest, to varying degrees
• Four characteristics that distinguish them from
  normal cells
• Uncontrolled proliferation,
• Dedifferentiation and loss of function,
• Invasiveness,
• Metastasis.

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The genesis of a cancer cell

• A normal cell turns into a cancer cell because of
  one or more mutations in its DNA, which can be
  inherited or acquired.
• The development of cancer is a complex multistage
  process, involving not only more than one genetic
  change but also other epigenetic factors
  (hormonal action, co-carcinogen and tumor
  promoter effects, etc)

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Cont.

• There are two main categories of genetic change
  that lead to cancer
• The activation of proto-oncogenes to oncogenes
• 2. The inactivation of tumor suppressor genes

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Activation of proto-oncogenes to oncogenes

• Proto-oncogenes are genes that normally control
• cell division,
• apoptosis
• differentiation
• But can be converted to oncogenes by viral or
  carcinogen action.

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Inactivation of tumor suppressor genes (TSG)

• Normal cells contain tumor suppressor genes
  (anti-oncogenes) eg p53
• TSG have the ability to suppress malignant
  changes
• The loss of function of tumor suppressor genes
  can be the critical event in carcinogenesis

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The special characteristics of cancer cells
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Cancer treatment strategies

• Cancer treatment strategies includes
• 1. Goals of treatment
• 2. Indication for treatment
• 3. Tumor susceptibility and the growth cycle

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1. Goals of treatment

• (A) The ultimate goal of cancer treatment is a
  CURE (Eradication of every neoplastic cells). If
  cure is not attainable, then the goal became
• (B) CONTROL OF THE DISEASE (stop the cancer from
  enlarging and spreading) to extent survival and
  QoL of the patient.

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• At this step, the cancer being treated as a
  chronic disease. The neoplastic cell burden is
  initially reduced (debulked), either by surgery
  and / or by radiation followed by chemotherapy,
  immunotherapy, or combination of these treatment
  modalities.
• (C) In advanced stages of cancer, the likelihood
  of controlling the cancer is far from reality and
  the goal become PALLIATION (alleviation of
  symptoms)

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2. Indications for treatment

• Treatment modalities depend on the extent of the
  cancer
• For Localized cancer is mainly treated by surgery
• For Loco-regional disease by radiotherapy
• For widespread disease by chemotherapy, hormonal
  therapy, or biological therapy

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Indications for chemotherapy

• Chemotherapy indicated when neoplasms are
  disseminated and are not responsive to surgery
• Treatment modality with chemotherapy may be
• Adjuvant chemotherapy
• Neoadjuvant chemotherapy
• Maintenance chemotherapy
• Induction chemotherapy

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• Adjuvant chemotherapy - Chemo is used as
  supplemental treatment to attack micrometastases
  following surgery radiation

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• Neoadjuvant chemotherapy Chemotherapy given
  prior to the surgical procedure in an attempt to
  shrink the tumor
• Induction chemotherapy is chemotherapy given
  before the initiation of another treatment (eg
  radiation, surgery, chemoradiation etc)
• Maintenance chemotherapy Chemotherapy given in
  lower doses to assist in prolonging a remission

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3. Tumor susceptibility and the growth cycle

• The fraction of tumor cells that are in the
  replicative cycle (growth fraction) influences
  their susceptibility to most cancer
  chemotherapeutic agents
• Rapidly dividing cells are generally more
  sensitive to anticancer drugs while slowly
  proliferating cells are less sensitive to
  chemotherapy

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• In general, nonproliferating cells (those in G0
  phase) usually survive the toxic effects of many
  anticancer drugs

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Treatment protocols

• Combination-drug chemotherapy is more successful
  than single-drug treatment in most of the cancer
• Combined drugs should be based on
• Qualitatively different toxicities
• Different mechanism of action
• Different molecular sites of action

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• Advantage of drug combination
• Provide maximal cell killing within the range of
  tolerated toxicity
• Are effective against a broader range of cell
  lines in the heterogeneous tumor population
• May delay of prevent the development of resistant
  cell lines .

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• Many cancer treatment protocols have been
  developed
• Each one is applicable to a particular neoplastic
  state
• They are usually identified by an acronym
• For example a common regimen called POMP, used
  for treatment of ALL consists of Prednisone,
  Oncovin (vincristine), Methotrexate, and
  Purinethol (mercaptopurine)
• Therapy is scheduled intermittently (appr 21 days
  apart) to allow recovery of patients immune
  system.

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Problems associated with Chemo.

• Narrow therapeutic index (highly toxic)
• Resistant of tumor cells to anticancer agents
• Multidrug resistance (MDR) eg P-gp
• Treatment induced tumors

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Treatment approaches

• Main approaches in cancer treatment
• Surgery
• Radiation
• Chemotherapy
• Immunotherapy
• Targeted therapy
• The role of each of these depends on the type of
  tumor and the stage of its development.
• Chemotherapy can be used on its own or as an
  adjunct to other forms of therapy

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• Chemotherapy of cancer, as compared with that of
  bacterial disease, presents a difficult problem.
• In biochemical terms, microorganisms are both
  quantitatively and qualitatively different from
  human cells
• However cancer cells and normal cells are so
  similar in many respects that it is more
  difficult to find general, exploitable,
  biochemical differences between them.

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General principles of action of cytotoxic
anticancer drugs
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• One of the major difficulties in the use of
  cancer chemotherapy is that a tumor is usually
  far advanced before it is diagnosed.
• Most currently used anticancer drugs, in
  particular those which are 'cytotoxic', affect
  only one characteristics of cancer cells i.e
  uncontrolled proliferation

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• Thus, they are antiproliferative
• They have no specific inhibitory effect on
• Invasiveness,
• Loss of differentiation or
• The tendency to metastasize

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• For many, their antiproliferative action results
  mainly from an action during S phase of the cell
  cycle, and the resultant damage to DNA initiates
  apoptosis
• Furthermore, because their main effect is on cell
  division, they will affect all rapidly dividing
  normal tissues and thus they are likely to
  produce, to a greater or lesser extent, the
  following general toxic effects

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Cont

• Bone marrow toxicity (myelosuppression) with
  decreased leucocyte production and thus decreased
  resistance to infection
• Impaired wound healing
• Loss of hair (alopecia)
• Damage to gastrointestinal epithelium
• Depression of growth in children
• Sterility
• Teratogenicity

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Cont

• They can also, in certain circumstances, be
  carcinogenic (i.e. they may themselves cause
  cancer).
• In addition, if there is rapid cell destruction
  with extensive purine catabolism, urates may
  precipitate in the renal tubules and cause kidney
  damage.

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• Finally, virtually all cytotoxic drugs produce
  severe nausea vomiting, which has been called
  'the inbuilt deterrent' to patient compliance in
  completing a course of treatment with these
  agents.
• Some compounds have particular toxic effects that
  are specific for them.

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Cell cycle and action of chemotherapeutic drugs
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Cont.

• Many chemotherapeutic drugs inhibit progression
  of cell cycle.
• An understanding of cell cycle kinetics is
  essential for the proper use of anticancer drugs.
  
• The cell division cycle is the fundamental
  mechanism to maintain tissue homeostasis.
• The cell cycle can be divided into 4 phases

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Cell cycle phases

• (1) Growth phase 1 (G1- phase) a phase that
  precedes DNA synthesis
• (2) Synthesis phase (S-Phase) a DNA synthesis
  phase
• (3) growth phase 2 (G2-phase) an interval
  following the termination of DNA synthesis
• (4) mitotic phase (M phase) the phase in which
  the cell, containing a double complement of DNA,
  divides into two daughter G1 cells.

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Cont,,,

• Each of these daughter cells may immediately
  re-enter the cell cycle or pass into a
  nonproliferative stage, referred to as G0.
• Chemotherapeutic drugs can be divided into three
  classes based on their relationship with cell
  cycle
• 1. Cell cycle specific
• 2. Cell cycle non-specific
• 3. Non-cell cycle active e.g. hormones.
•  

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Characteristics of chemotherapeutic drugs

• Most anticancer drugs are cytotoxic agents that
  inhibit the synthesis of new genetic material or
  cause irreparable damage to DNA itself.
• Anticancer drugs often have a narrower
  therapeutic index and a greater potential for
  causing harmful side effects than other drugs.

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Cont.

• Anticancer Drugs are most effective when used in
  combination.
• Most of the side effects of anticancer drugs are
  manageable

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Anticancer drug classification

• Cell cycle specific
• Cell cycle non-specific
• None cell cycle active (e.g Hormones)

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Target of anticancer agents

• There are three targets associated with the use
  of the most commonly-used anticancer agents.
• Damage the DNA of the affected cancer cells
• Inhibit the synthesis of new DNA strands to stop
  the cell from replicating
• Stop mitosis or the actual splitting of the
  original cell into two new cells.

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DRUGS USED IN CANCER CHEMOTHERAPY
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Outline of mechanism of action

• 1. Cytotoxic drugs
• Alkylating agents and related compounds- act by
  forming covalent bonds with DNA and thus impeding
  DNA replication
• Examples of alkylating agents are

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• Cisplatin
• Oxaliplatin
• Carboplatin
• Chlorambucil
• Cyclophosphamide
• Mechlorethamine,
• Melphalan
• Carmustine
• Busulphan
• Decarbazine
• Procarbazine

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• Antimetabolites - block or subvert one or more of
  the metabolic pathways involved in DNA synthesis

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• Cytotoxic antibiotics, i.e. substances of
  microbial origin that prevent mammalian cell
  division
• Plant derivatives (vinca alkaloids, taxanes,
  campothecins) most of these specifically affect
  microtubule function and hence the formation of
  the mitotic spindle.

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• 2. Hormones
• The most important are steroids, namely
• Glucocorticoids,
• Estrogens
• Androgens
• Ddrugs that suppress hormone secretion or
  antagonize hormone action

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I. CYTOTOXIC DRUGS
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1. Alkylating agents and related compounds

• Cross-link 2 strands of DNA leading to impairment
  of DNA replication and RNA transcription.
• Their principal effect occurs during DNA
  synthesis the resulting DNA damage triggers
  apoptosis.
• Unwanted effects include myelosuppression,
  sterility and risk of non-lymphocytic leukaemia

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• The main alkylating agents are
• Nitrogen mustards, e.g. cyclophosphamide
• Cyclophosphamide is probably the most commonly
  used alkylating agent.
• It is inactive until metabolised in the liver by
  the P450 mixed function oxidases
• It has a pronounced effect on lymphocytes and can
  be used as an immunosuppressant

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Cont

• It is usually given p.o or by I/V injection but
  may also be given by I/M
• Important toxic effects are
• nausea and vomiting,
• bone marrow depression
• haemorrhagic cystitis

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• This last effect (which also occurs with the
  related drug ifosfamide) is caused by the
  metabolite acrolein and can be ameliorated by
  increasing fluid intake and administering
  compounds that are sulfhydryl donors, such as
  N-acetylcysteine or mesna (sodium-2-mercaptoethane
  sulfonate).
• These agents interact specifically with acrolein,
  forming a non-toxic compound.

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• Cyclophosphamide is activated to give
  aldophosphamide, which is then converted to
  phosphoramide mustard (the cytotoxic molecule)
  and acrolein (which causes bladder damage that
  can be ameliorated by mesna)
• Cyclophosphamide myelosuppression affects
  particularly the lymphocytes.

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• Nitrosoureas, e.g. Lomustine,
• they are lipid soluble and can, therefore, cross
  the blood-brain barrier, may be used against
  tumors of the brain and meninges.
• However, most nitrosoureas have a severe
  cumulative depressive effect on the bone marrow
  that starts 3-6 weeks after initiation of
  treatment.

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• Busulphan
• Busulphan has a selective effect on the bone
  marrow, depressing the formation of granulocytes
  and platelets in low dosage and red cells in
  higher dosage.
• It has little or no effect on lymphoid tissue or
  the gastrointestinal tract.
• It is used in chronic granulocytic leukemia.

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• Cisplatin
• Cisplatin is a water-soluble compound
• Its action is analogous to that of the alkylating
  agents
• Cisplatin is given by slow intravenous injection
  or infusion.
• It is seriously nephrotoxic unless regimens of
  hydration and diuresis are instituted.
• It has low myelotoxicity but causes very severe
  nausea and vomiting

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• The 5-HT3-receptor antagonists (e.g. ondansetron,
  granisetron, dolasetron, and palonosetron are
  very effective in preventing this and have
  transformed cancer chemotherapy with cisplatin.
• Tinnitus and hearing loss in the high frequency
  range may occur, as may peripheral neuropathies,
  hyperuricaemia and anaphylactic reactions
• It has revolutionized the treatment of solid
  tumors of the testes and ovary.

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• Carboplatin is a derivative of cisplatin.
• It causes less nephrotoxicity, neurotoxicity and
  ototoxicity, and less severe nausea and vomiting
  than cisplatin, but is more myelotoxic.
• Dacarbazine
• Dacarbazine, a pro-drug, is activated in the
  liver, and the resulting compound is subsequently
  cleaved in the target cell to release an
  alkylating derivative.
• Unwanted effects include myelotoxicity and severe
  nausea and vomiting.

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ii. Antimetabolites
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Folate antagonists

• The main folate antagonist is methotrexate
• it is one of the most widely used antimetabolites
  in cancer chemotherapy.
• Methotrexate inhibits dihydrofolate reductase,
  preventing generation of tetrahydrofolate the
  main result is interference with thymidylate
  synthesis

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• Methotrexate is usually given p.o but can also be
  given I/M, I/V or intrathecally.
• The drug has low lipid solubility and thus does
  not readily cross the blood-brain barrier.
• It is actively taken up into cells by the
  transport system used by folate and is
  metabolized to polyglutamate derivatives, which
  are retained in the cell for weeks (months in
  some tissues) in the absence of extracellular
  drug.

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• Unwanted effects are
• depression of the bone marrow and damage to the
  epithelium of the gastrointestinal tract.
• Pneumonitis can occur
• In addition, when high-dose regimens are used,
  there may be nephrotoxicity, caused by
  precipitation of the drug or a metabolite in the
  renal tubules

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Cont

• High-dose regimens (doses 10 times greater than
  the standard doses), sometimes used in patients
  with methotrexate resistance, must be followed by
  'rescue' with folinic acid

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Pyrimidine analogues

• Eg, of pyridine analogue is 5-fluorouracil
• Fluorouracil is converted to a fraudulent
  nucleotide and inhibits thymidylate synthesis.
• Fluorouracil is usually given parenterally
• 5-FU is employed primarily in the treatment of
  slowly growing solid tumors e.g Colorectal,
  breast, ovarian, pancreatic, and gastric
  carcinomas.
• Topically for treatment of basal cell carcinomas

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• Rapidly metabolized in liver, lung kidney
• The dose of 5-FU MUST be adjusted in case of
  impaired hepatic function
• Metabolized by dihydropyrimidine dehydrogenase
  (DPD), a polymorphic enzyme
• The main unwanted effects are nausea, vomiting,
  diarrhea, alopecia, ulceration of oral GI
  mucosa, myelotoxicity and anorexia.
• Cerebellar disturbances can occur.

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Cytarabine

• Is an analog of 2-deoxycytidine
• in its trisphosphate form inhibits DNA
  polymerase
• Major clinical use is in acute nonlymphocytic
  leukemia in combination with 6-TG and
  daunorubicin
• Adverse effect includes nausea, vomiting,
  diarrhea myelosuppression

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Purine analogues

• The main anticancer purine analogues include
• Fludarabine
• Pentostatin
• Cladribine
• 6-Mercaptopurine (6-MP)
• 6-Tioguanine (6-TG)

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• Mercaptopurine
• is converted into fraudulent nucleotide.
• Fludarabine in its trisphosphate form inhibits
  DNA polymerase
• Is used principally in the maintenance of
  remission in ALL
• Its bioavailability can be reduced by FPM in the
  liver
• In the liver, 6-MP is converted to 6-methyl-MP
  derivative or to thiouric acid (an inactive
  metabolites)

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• Note the latter reaction is catalyzed by
  Xanthine oxidase (XO).
• Because the XO inhibitor, allopurinal, is
  frequently used to reduce hyperuricemia in Cancer
  patients receiving chemotherapy, it is important
  to decrease the dose of 6-MP by 75 in these
  patients to avoid accumulation of the drug
• The principal toxicity of 6-MP is
  myelosuppression. Also N, V, D jaundice.

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iii. Cytotoxic antibiotics
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Cont.

• Antitumour antibiotics produce their effects
  mainly by direct action on DNA
• They include
• Doxorubicin
• Dactinomycin
• Bleomycins
• Mitomycin
• Procarbazine
• Hydroxycarbamide

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Doxorubicin

• Doxorubicin inhibits DNA and RNA synthesis the
  DNA effect is mainly through interference with
  topoisomerase II action.
• It is used in combination with other agents for
  treatment of sarcomas and a variety of carcinomas
  e.g breast and lung Ca as well as for treatment
  of ALL and lymphomas.

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• Must be administered by I/V inactivated in the
  GI tract
• Do not penetrate BBB or testes
• Undergo extensive hepatic metabolism bile is
  the major route of excretion
• Dose adjustment is required in hepatic impairment
  
• Due to dark red color of anthracycline drugs, the
  drug also impart a red color to the urine.

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• Unwanted effects include
• Irreversible, dose-dependent cardiotoxicity is
  the most serious adverse reaction (more common
  with doxorubicin daunorubicin than with
  idarubicin epirubicin)
• Irradiation of the thorax increase the risk of
  cardiotoxicity
• Addition of trastuzumab to protocols with
  doxorubicin or epirubicin increases CHF.

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Other adverse effects includes

• nausea and vomiting,
• myelosuppression
• severe hair loss (alopecia)
• Increased skin pigmentation
• Stomatitis

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Bleomycin

• Bleomycin causes fragmentation of DNA chains.
• It is cell cycle specific acting on G2 phase
• It is primarily in the treatment of testicular
  cancers in combination with vinblastine or
  etoposide
• Response rates are close to 100 if cisplatin is
  added to the regimen.

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• Most of the parent drug is excreted unchanged
  into the urine by GF dose adjustment in RF.
• Unwanted effects include
• fever,
• allergies,
• mucocutaneous reactions
• pulmonary fibrosis
• There is virtually no myelosuppression.

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Dactinomycin

• Dactinomycin intercalates in DNA, interfering
  with RNA polymerase and inhibiting transcription.
• It also interferes with the action of
  topoisomerase II.
• It is used in combination with surgery and
  vincristine for the treatment of Wilms tumors
  (nephroblastoma)

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• Used in combination with MTX for treatment of
  gestational choriocarcinoma
• Unwanted effects include nausea, vomiting
  myelosuppression.

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iv. plant derivatives
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Vinca alkaloids

• The main vinca alkaloids are
• vincristine,
• vinblastine
• Venorelbine
• They act by binding to tubulin and inhibiting its
  polymerisation into microtubules, which prevents
  spindle formation in mitosing cells and causes
  arrest at metaphase.

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• Their effects only become manifest during
  mitosis.
• They also inhibit other cellular activities that
  involve the microtubules, such as leucocyte
  phagocytosis and chemotaxis as well as axonal
  transport in neurons.
• They are generally administered in combination
  with other drugs
• Although similar in structure, their therapeutic
  indications are different

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• Vincristine is used in treatment of ALL in
  children, Wilms tumors, and Hodgkin and
  non-Hodgkin lymphomas
• Vinblastine in combination with bleomycin and
  cisplatin is used in treatment of metastatic
  testicular carcinoma
• Venorelbine is beneficial in the treatment of
  advanced non-small cell lung cancer, either as a
  single agent or in combination with cisplatin.

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• The vinca alkaloids are relatively non-toxic.
• Vincristine has very mild myelosuppressive
  activity but causes paraesthesias (sensory
  changes) and muscle weakness fairly frequently.
• Vinblastine is less neurotoxic but causes
  leucopenia, while vindesine has both moderate
  myelotoxicity and neurotoxicity.
• Hyperuricemia is common administer XO inhibitors

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Taxanes

• The taxanes paclitaxel and docetaxel act on
  microtubules, stabilising them (in effect
  'freezing' them) in the polymerised state.
• This has repercussions similar to those described
  above for the vinca alkaloids.
• Paclitaxel is given by intravenous infusion and
  docetaxel by mouth.

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• Both have a place in the treatment of breast
  cancers
• paclitaxel, given with carboplatin, is the
  treatment of choice for ovarian cancer.
• Paclitaxel in combination with cisplatin have
  favourable results in treatment of non-small cell
  lung cancer

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Unwanted effects

• Unwanted effects, which can be serious, include
  bone marrow suppression (neutropenia) and
  cumulative neurotoxicity.
• Resistant fluid retention (particularly oedema
  of the legs) can occur with docetaxel.
• Hypersensitivity to both compounds is liable to
  occur and requires pretreatment with
  corticosteroids and antihistamines.

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Etoposide

• Etoposide is derived from mandrake root.
• Its mode of action is not clearly known but it
  may act by inhibiting mitochondrial function and
  nucleoside transport, as well as having an effect
  on topoisomerase II similar to that seen with
  doxorubicin.
• Unwanted effects include nausea and vomiting,
  myelosuppression hair loss.

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Campothecins

• The campothecins irinotecan and topotecan bind to
  and inhibit topoisomerase I, high levels of which
  occur throughout the cell cycle.
• Diarrhoea and reversible bone marrow depression
  occur but, in general, these drugs have fewer
  unwanted effects than most other anticancer
  agents.

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Clinical uses

• First-line therapy (with 5-FU and leucovorin) for
  metastatic colorectal cancer (CRC)
• It is also indicated for CRC that has recurred or
  progressed following initial fluorouracil-based
  therapy
• Off-label advanced ovarian cancer, glioblastoma
  multiforme, NSCLC

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Enzyme (L-asparaginase)

• Asparaginase is an enzyme that catalyzes the
  hydrolysis of l-asparagine to l-aspartic acid
  and ammonia.
• Isolated from different types of bacteria,
  including E. coli
• They inhibit protein synthesis in tumor cells by
  depriving them of the amino acid asparagine

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• This drug is phase specific, with the greatest
  activity in the G1 phase of the cell cycle.
• Clinical use is confined presently to acute
  lymphocytic leukemia
• Asparaginase products may produce
• Acute hypersensitivity reactions
• Hypotension,
• Sweating, 
• Bronchospasm, and 
• Urticaria.

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2. HORMONES

• Tumors that are steroid hormone-sensitive may be
• Hormone responsive regresses following
  treatment with a specific hormone
• Hormone dependent regresses following removal
  of hormone stimulus
• Both hormone responsive and dependent

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Overview of Targeted therapy

• Targeted therapy is a type of cancer treatment
  that uses drugs or other substances to precisely
  identify and attack certain types of cancer cells
• A targeted therapy can be used by itself or in
  combination with other treatments,

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Targeted therapy includes

• Hormone therapies, 
• Signal transduction inhibitors,
• Gene expression modulators,
• Apoptosis inducers,
• Angiogenesis inhibitors,
• Immunotherapies,
• Toxin delivery molecules

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