Ahmed Group Lecture 23 Chemotherapeutic agents and radiation therapy Lecture 23.

Ahmed GroupAhmed GroupLecture 23Lecture 23

Chemotherapeutic agents and radiation therapy

Lecture 23


Chemotherapeutic agents and radiation therapy

• Classes of agents• Mechanisms of action• The oxygen effect in chemotherapy• Multiple drug resistance• Interactions of chemotherapeutic agents with radiation therapy (chemoradiation therapy)• Photodynamic therapy


- Many of the techniques and concepts used inchemotherapy:

• quantitative tumor assay systems• the concept of cell cycle and sensitivity changes through the cell cycle;• population kinetics

- Terms:

• growth fraction,• dose

Inspired and developed initially by and for radiation biologists:


Chemotherapy

The term introduced by Paul Erlich

1. Salvarsan, the savior of mankind. Described the use of chemicals to treat parasites-arsenic compound effective against trypanosome and syphilis. 2. Penicillin-WWII3. Alkylating agents-WWI and WWII4. Anticancer drugs-methotrexate and cyclophosphamide5. Combination chemotherapy of lymphocytic leukemia in the early 1960s. Multiple drugs with different toxicities could be used in combination to cure tumors.


Today a wide variety of anticancer agents are used in clinical oncology. They have beenproven effective for:

•choriocarcinoma,•acute lymphocytic leukemia of childhood•Hodgkin’s disease•certain non-Hodgkin’s lymphomas,•some germ cell tumors of testes

Chemotherapy


Chemotherapy of cancer – is the treatment and control of metastatic disease, a cancerthat has become systemic and out of control.

There are 13 types of cancer for which cures are claimedby chemotherapy; this accounts for about 10% of allcancers.Comparison: 12.5% of cancers are cured by radiationtherapy

½ x ½ x ½ rule


Biologic basis of chemotherapy

Anticancer drugs work by affecting DNA synthesis or function, they do not normally kill resting cells;The effectiveness of the drug is limited by the growthfraction of tumor, thus, small rapidly proliferating tumorsare more responsive to chemotherapy than the large ones. Growth fraction decreases as tumor size increases.



Cell-cycle specific, or phase-specific agents;Cell-cycle nonspecific or phase-non-specific agents


• Classes of agents• Mechanisms of action• The oxygen effect in chemotherapy• Multiple drug resistance• Interactions of chemotherapeutic agents with

radiation therapy (chemoradiation therapy)

• Photodynamic therapy


Classes of agents and mode of action

Four categories of most commonly usedchemotherapeutic agents:

• Alkylating agents;• Antibiotics;• Antimetabolites• Miscellaneous: platinum complexes procarbazine plant alkaloids


Classes of agents and mode of action


Classes of agentsAlkylating agents

Highly reactive, substitute alkyl groups for hydrogen atoms of organic compounds (ex. DNA).

Five classes: 1. Nitrogen mustard derivatives 2. Ethylenimine derivatives 3. Alkyl sulfonates 4. Triazine derivatives 5. Nitrozoureas

Most of them contain more than one alkylating group and thereforeconsidered polyfunctional alkylating agents.As a class alkylating agents are considered to be cell-cycle nonspecific


Classes of agents

Antibiotics

The clinically useful antibiotics are natural productsof various strains of the soil fungus Streptomyces.The directly bind DNA, and inhibit DNA and RNA synthesis

As a class they behave as cell-cycle nonspecific agents.

Examples: Doxorubicin, Actinomycin D, Bleomycin, Mitomycin C


Classes of agentsPlant Alkaliods

Vinca alkaloid. Produced from the common periwinkle plant.The clinically useful alkaloids are large complex molecules thatexert their antitumor effect by binding to cellular microtubular proteins and inhibiting microtubular polymerization, the essential compounds of the mitotic spindle.Effect - mitotic arrest.

Taxanes - products of the yew tree. The toxicity of the leaves orbark is caused by alkaloids taxanes.Paclitaxel – is a natuarla product, a new class of antineoplastic agents, the taxanes, that targets the microtubules. The taxanes are potent microtubule-stabilizing agents, promotersof microtubule assemly. This is in contrast to vinca.They block cells in G2/M phases of the cell cycle.


Classes of agentsAntimetabolites

Analogues of normal metabolites. The interact with enzymesand damage cells by:

1. Substituting for a metabolite normally incorporated into a keymolecule2. Competing successfully with a normal metabolite for occupation of the catalytic site of a key enzyme3. Competing with a normal metabolite that acts at an enzyme regulatory site to alter the catalytic rate of the enzyme


Classes of agents

Miscellaneous agents

Examples: Methylhydrazine, nitrosoureas, hydroxyurea,cis-platinum, taxanes

Hydroxyurea. First synthesized in 1869 and was found to bebone-marrow suppressive in 1928.Used in treatment of cancer in the 1960s.It is an inhibitor of ribonucleotide reductase, an enzyme essential to DNA symthesis, and is consequently specifically cytotoxicto cells in the S phase;

Cis-platinum. is an inorganic complex-platinum surrounded by chlorine and ammonium ions. Cell-cycle nonspecific. Binds toDNA causing cross-linking


Classes of agents and mode of actionSummary


Classes of agents

Dose-response relationship for six commonly used chemotherapeutic agents


Classes of agents.Mechanisms of action

Another characteristic of chemotherapy agents is that the sensitivity to cell killingvaries enormously among cell types.


Classes of agents. Mechanisms of actionSublethal and potentially lethal damage repair

Sublethal damage repair-an increase in survival if a dose of radiation(or other cytotoxic agent) is divided into fractions. It tends to correlatewith the shoulder of the acute dose-response curve, but this is not necessarily always true. Repair of potentially lethal damage is manifested as an increase in survival if cells are held in a nonproliferative state for some time after treatment.

Similar studies have been performed with a variety of chemotherapeuticagents.

Next slide: potentially lethal damage repair is a significant factor in theantibiotics bleomycin and doxorubicin


Classes of agents.Mechanisms of action

Sublethal and potentiallylethal damage repair


The oxygen effect in chemotherapy

The presence or absence of oxygen has a dramatic influenceon the proportion of cells surviving a given dose of X-rays.Situation with chemotherapeutic agents is more complicated.

Some agents, such as bleomycin, are more toxic to oxygenatedcells than to chronically hypoxic cells.


The oxygen effect in chemotherapyDose-response curves for cells exposed to graded concentrationsof bleomycin in the presence or absence of oxygen


The oxygen effect in chemotherapy

• Some of the drugs are more toxic to hypoxic that to aerated conditions;

• Some of the drugs are more toxic to aerated conditions

• A third group of drugs appear to be equally cytotoxic to aerated or hypoxic cells


Resistance to chemotherapy andhypoxic cytotoxins


Drug resistance

During prolong exposureto a cytostatic drug cellsbecome resistant to thedrug and the tumorbecomes unresponsive.


Drug resistanceUnderlying this problem are genetic changes that could be seensometimes in chromosome preparations


Drug resistanceA debatable issue is whether cells that acquired resistance to chemotherapeutic agents are also resistant to radiation.Laboratory data show that the acquiring of resistance to a drug does not necessarily result in radioresistance.


Comparison of chemotherapeuticagents with radiation

There is much greater variationof sensitivity to chemotherapeuticagents than there is to radiation.

The response of one cell line tonine different cytotoxic agents


Comparison of chemotherapeuticagents with radiation

There is much greater variationof sensitivity to chemotherapeuticagents than there is to radiation.

Figure shows the widely differentresponse to CCNU of three clonesderived from a common astrocytoma cell line


Adjunct use of chemotherapeutic agents with radiation

Spacial cooperation is the rationale for the combination ofradiation and chemotherapy


Adjunct use of chemotherapeutic agents with radiation


Photodynamic therapy

Cancer treatment using light to activate a photosensitizingagent, thereby releasing cytotoxic free radicals.When photosensitizers are exposed to a specific wavelengthof light, they produce a form of oxygen that kills nearby cells.

Each photosensitizer is activated by light of a specific wavelength. This wavelength determines how far the light can travel into the body.Thus, doctors use specific photosensitizers and wavelengths of light totreat different areas of the body with PDT.


How is PDT used to treat cancer?

In the first step of PDT for cancer treatment, a photosensitizingagent is injected into the bloodstream. The agent is absorbed bycells all over the body, but stays in cancer cells longer than it doesin normal cells. Approximately 24 to 72 hours after injection whenmost of the agent has left normal cells but remains in cancer cells,the tumor is exposed to light. The photosensitizer in the tumorabsorbs the light and produces an active form of oxygen thatdestroys nearby cancer cells. In addition to directly killing cancercells, PDT appears to shrink or destroy tumors in two other ways.The photosensitizer can damage to blood vessels in the tumor,thereby preventing the cancer from receiving necessary nutrients. In addition, PDT may activate the immune system to attack the tumor cells.



The light used for PDT can come from a laser or other sources of light. Laser light can be directed through fiber optic cables (thin fibers that transmit light) to deliver light to areas inside the body. For example, a fiber optic cable can be inserted through an endoscope (a thin, lighted tube used to look at tissues inside the body) intothe lungs or esophagus to treat cancer in these organs. Other light sources include light-emitting diodes (LEDs), which may be used for surface tumors, such as skin cancer.

PDT is usually performed as an outpatient procedure. PDT may also be repeated and may be used with other therapies, such as surgery, radiation or chemotherapy.


Ahmed Group Lecture 23 Chemotherapeutic agents and radiation therapy Lecture 23.

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