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

2. Ahmed Group 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

3. Ahmed Group Lecture 23 - Many of the techniques and concepts used in chemotherapy: 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:

4. Ahmed Group Lecture 23 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-WWII 3. Alkylating agents-WWI and WWII 4. Anticancer drugs-methotrexate and cyclophosphamide 5. Combination chemotherapy of lymphocytic leukemia in the early 1960s. Multiple drugs with different toxicities could be used in combination to cure tumors.

5. Ahmed Group Lecture 23 Today a wide variety of anticancer agents are used in clinical oncology. They have been proven effective for: choriocarcinoma, acute lymphocytic leukemia of childhood Hodgkin’s disease certain non-Hodgkin’s lymphomas, some germ cell tumors of testes Chemotherapy

6. Ahmed Group Lecture 23 Chemotherapy of cancer – is the treatment and control of metastatic disease, a cancer that has become systemic and out of control. There are 13 types of cancer for which cures are claimed by chemotherapy; this accounts for about 10% of all cancers. Comparison: 12.5% of cancers are cured by radiation therapy ½ x ½ x ½ rule

7. Ahmed Group Lecture 23 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 growth fraction of tumor, thus, small rapidly proliferating tumors are more responsive to chemotherapy than the large ones. Growth fraction decreases as tumor size increases.

8. Ahmed Group Lecture 23 Biologic basis of chemotherapy Cell-cycle specific, or phase-specific agents; Cell-cycle nonspecific or phase-non-specific agents

9. Ahmed Group Lecture 23 Biologic basis of chemotherapy

10. Ahmed Group Lecture 23 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

11. Ahmed Group Lecture 23 Classes of agents and mode of action Four categories of most commonly used chemotherapeutic agents: Alkylating agents; Antibiotics; Antimetabolites Miscellaneous: platinum complexes procarbazine plant alkaloids

12. Ahmed Group Lecture 23 Classes of agents and mode of action

13. Ahmed Group Lecture 23 Classes of agents Alkylating 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 therefore considered polyfunctional alkylating agents. As a class alkylating agents are considered to be cell-cycle nonspecific

14. Ahmed Group Lecture 23 Classes of agents Antibiotics The clinically useful antibiotics are natural products of 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

15. Ahmed Group Lecture 23 Classes of agents Plant Alkaliods Vinca alkaloid. Produced from the common periwinkle plant. The clinically useful alkaloids are large complex molecules that exert 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 or bark 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, promoters of microtubule assemly. This is in contrast to vinca. They block cells in G2/M phases of the cell cycle.

16. Ahmed Group Lecture 23 Classes of agents Antimetabolites Analogues of normal metabolites. The interact with enzymes and damage cells by: 1. Substituting for a metabolite normally incorporated into a key molecule 2.Competing successfully with a normal metabolite for occupation of the catalytic site of a key enzyme 3.Competing with a normal metabolite that acts at an enzyme regulatory site to alter the catalytic rate of the enzyme

17. Ahmed Group Lecture 23 Classes of agents Miscellaneous agents Examples: Methylhydrazine, nitrosoureas, hydroxyurea, cis-platinum, taxanes Hydroxyurea. First synthesized in 1869 and was found to be bone-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 cytotoxic to cells in the S phase; Cis-platinum. is an inorganic complex-platinum surrounded by chlorine and ammonium ions. Cell-cycle nonspecific. Binds to DNA causing cross-linking

18. Ahmed Group Lecture 23 Classes of agents and mode of action Summary

19. Ahmed Group Lecture 23 Classes of agents Dose-response relationship for six commonly used chemotherapeutic agents

20. Ahmed Group Lecture 23 Classes of agents. Mechanisms of action Another characteristic of chemotherapy agents is that the sensitivity to cell killing varies enormously among cell types.

21. Ahmed Group Lecture 23 Classes of agents. Mechanisms of action Sublethal 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 correlate with 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 chemotherapeutic agents. Next slide: potentially lethal damage repair is a significant factor in the antibiotics bleomycin and doxorubicin

22. Ahmed Group Lecture 23 Classes of agents. Mechanisms of action Sublethal and potentially lethal damage repair

23. Ahmed Group Lecture 23 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

24. Ahmed Group Lecture 23 The oxygen effect in chemotherapy The presence or absence of oxygen has a dramatic influence on 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 oxygenated cells than to chronically hypoxic cells.

25. Ahmed Group Lecture 23 The oxygen effect in chemotherapy Dose-response curves for cells exposed to graded concentrations of bleomycin in the presence or absence of oxygen

26. Ahmed Group Lecture 23 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

27. Ahmed Group Lecture 23 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

28. Ahmed Group Lecture 23 Resistance to chemotherapy and hypoxic cytotoxins

29. Ahmed Group Lecture 23 Drug resistance During prolong exposure to a cytostatic drug cells become resistant to the drug and the tumor becomes unresponsive.

30. Ahmed Group Lecture 23 Drug resistance Underlying this problem are genetic changes that could be seen sometimes in chromosome preparations

31. Ahmed Group Lecture 23 Drug resistance A 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.

32. Ahmed Group Lecture 23 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

33. Ahmed Group Lecture 23 Comparison of chemotherapeutic agents with radiation There is much greater variation of sensitivity to chemotherapeutic agents than there is to radiation. The response of one cell line to nine different cytotoxic agents

34. Ahmed Group Lecture 23 Comparison of chemotherapeutic agents with radiation There is much greater variation of sensitivity to chemotherapeutic agents than there is to radiation. Figure shows the widely different response to CCNU of three clones derived from a common astrocytoma cell line

35. Ahmed Group Lecture 23 Adjunct use of chemotherapeutic agents with radiation Spacial cooperation is the rationale for the combination of radiation and chemotherapy

36. Ahmed Group Lecture 23 Adjunct use of chemotherapeutic agents with radiation

37. Ahmed Group Lecture 23 Adjunct use of chemotherapeutic agents with radiation

38. Ahmed Group Lecture 23 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

39. Ahmed Group Lecture 23 Photodynamic therapy Cancer treatment using light to activate a photosensitizing agent, thereby releasing cytotoxic free radicals. When photosensitizers are exposed to a specific wavelength of 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 to treat different areas of the body with PDT.

40. Ahmed Group Lecture 23 How is PDT used to treat cancer? In the first step of PDT for cancer treatment, a photosensitizing agent is injected into the bloodstream. The agent is absorbed by cells all over the body, but stays in cancer cells longer than it does in normal cells. Approximately 24 to 72 hours after injection when most of the agent has left normal cells but remains in cancer cells, the tumor is exposed to light. The photosensitizer in the tumor absorbs the light and produces an active form of oxygen that destroys nearby cancer cells. In addition to directly killing cancer cells, 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. Photodynamic therapy

41. Ahmed Group Lecture 23 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. Photodynamic therapy