Cancer Chemotherapy-1

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Cancer Chemotherapy-1

• Dr. R. Senthil Kumar

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Etiolopathology
50.2 Rang
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Apoptosis

• Programmed cell death
• Cascade of proteases initiate process

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Characteristics of Cancer Cells

• The problem
• Cancer cells divide rapidly (cell cycle is
  accelerated)
• They are immortal
• Cell-cell communication is altered
• uncontrolled proliferation
• invasiveness
• Ability to metastasise

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The Goal of Cancer Treatments

• Curative
• Total irradication of cancer cells
• Curable cancers include testicular tumors, Wills
  tumor
• Palliative
• Alleviation of symptoms
• Avoidance of life-threatening toxicity
• Increased survival and improved quality of life
• Adjuvant therapy
• Attempt to eradicate microscopic cancer after
  surgery
• e.g. breast cancer colorectal cancer

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Six Established Rx Modalities

• Surgery
• Radiotherapy
• Chemotherapy
• Endocrine therapy
• Immunotherapy
• Biological therapy

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Major approaches to therapy of cancers
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Cell Cycle Growth, Division
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Cancer Chemotherapy

• After completion of mitosis, the resulting
  daughter cells have two options
• (1) they can either enter G1 repeat the cycle
  or
• (2) they can go into G0 and not participate in
  the cell cycle.
• Growth fraction - at any particular time some
  cells are going through the cell cycle whereas
  other cells are resting.
• The ratio of proliferating cells to cells in G0,
  is called the growth fraction.
• A tissue with a large percentage of proliferating
  cells few cells in G0 has a high growth
  fraction.
• Conversely, a tissue composed of mostly of cells
  in G0 has a low growth fraction.

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Cell Cycle Specific (CCS) Cell Cycle
Non-Specific Agents (CCNS)
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Log kill hypothesis

• According to the log-kill hypothesis,
  chemotherapeutic agents kill a constant fraction
  of cells (first order kinetics), rather than a
  specific number of cells, after each dose
• 1. Solid cancer tumors - generally have a low
  growth fraction thus respond poorly to
  chemotherapy in most cases need to be removed
  by surgery
• 2. Disseminated cancers- generally have a high
  growth fraction generally respond well to
  chemotherapy

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• Log kill hypothesis

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LOG kill hypothesis

• The example shows the effects of tumor burden,
  scheduling, initiation/duration of treatment on
  patient survival.
• The tumor burden in an untreated patient would
  progress along the path described by the RED LINE
  
• The tumor is detected (using conventional
  techniques) when the tumor burden reaches 109
  cells
• The patient is symptomatic at 1010-1011 cells
• Dies at 1012 cells.

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Cancer Chemotherapy

• Combinations of agents with differing toxicities
  mechanisms of action are often employed to
  overcome the limited cell kill of individual anti
  cancer agents. Each drug selected should be
  effective alone
• 3 advantages of combination therapy
• 1. Suppression of drug resistance - less chance
  of a cell developing resistance to 2 drugs than
  to 1 drug.
• 2. Increased cancer cell kill - administration of
  drugs with different mechanisms of action.
• 3. Reduced injury to normal cells - by using a
  combination of drugs that do not have overlapping
  toxicities, we can achieve a greater anticancer
  effect than we could by using any one agent alone.

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Resistance to Cytotoxic Drugs

• Increased expression of
• MDR-1 gene for a cell
• surface P-glycoprotein
• MDR-1 gene is involved
• with drug efflux
• Drugs that reverse MDR
• verapamil, quinidine,
• cyclosporine
• MDR increases resistance
• to natural drug products
• including the anthracyclines, vinca alkaloids,
  and epipodophyllotoxins

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Modes of Resistance to Anticancer Drugs
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General problems with anticancer drugs

• Most of them are antiproliferative, i.e. they
  damage DNA and so initiate apoptosis.
• They also affect rapidly dividing normal cells.
• This leads to toxicity which are usually severe.
• To greater or lesser extent the following
  toxicities are exhibits by all anticancer drugs.

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ADR of Antineoplastic Drugs in Humans
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Distinctive Toxicities of Some Anticancer Drugs
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Chemotherapeutic agents are much more toxic to
tissues that have a high growth fraction than to
tissues that have a low growth fraction.

• Proliferating cells are especially sensitive to
  chemotherapy because cytotoxic drugs usually act
  by disrupting DNA synthesis or mitosis, cellular
  activities that only proliferating cells carry
  out.
• Unfortunately, toxicity to the anticancer agents
  is to any rapidly dividing cells. (e.g. bone
  marrow, hair follicles, sperm forming cells).

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Prevention or Management of Drug Induced
toxicities

• The toxicities of some anticancer drugs can be
  well anticipated and hence be prevented by giving
  proper medications
• E.g. mesna is given to prevent hemorrhagic
  cystitis by cyclophosphamide
• Dexrazoxane, is used to reduce the risk of
  anthracycline-induced cardiomyopathy

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Anti-cancer drugs