Anti Tumor

CANCER CHEMOTHERAPY (Antineoplasia, Cytotoxic drugs)
Maria Immaculata Iwo SEKOLAH FARMASI ITB

1
Cancer?
Cancer is the uncontrolled growth of cells due to damage to DNA (mutations) and, occasionally, due to an inherited propensity to develop certain tumors. Cancer is basically a disease of cells characterized by shift in the control mechanisms that govern cell proliferation and differentiation. Usually express cell surface antigens that may be of normal type May exhibit qualitative or quantitative chromosomal abnormalities
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Cancer
A small subpopulation of cells within the tumor as tumor stem cell has ability to: - undergo repeated cycles of proliferation - migrate to distant sites in the body - colonize various organs in the process called metastasis - can express clonogenic or colony-forming capability - have chromosome abnormalities reflecting their genetic instability can survive more readily in the multicellular environment of the host
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Cancer?
The growth fraction ratio of proliferating cells to G0 Anticancer drugs are much more toxic to tissues with a high growth fraction than to tissues with a low growth fraction disseminated cancers (infiltration, metastases)
cause metabolic abnormalities illness and eventual death

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Causes of cancer
Multiple factors environmental exposure is probably most important. Chemical carcinogens : tobacco smoke, azo dyes, aflatoxins, asbestos, and benzene 90% carcinogens can be shown mutagenic (Ames test) Virus: certain DNA, RNA viruses
The cell cycle

4 phases of growth (G1, S, G2, M) high growth fraction 1 resting phase (G0) low growth fraction
The first phase called G1, is when the cell prepares to replicate its chromosomes. The second stage is called S, and in this phase DNA synthesis occurs and the DNA is duplicated. The next phase is the G2 phase, when the RNA and protein duplicate. The final stage is the M stage, which is the stage of actual cell division. In this final stage, the duplicated DNA and RNA split and move to separate ends of the cell, and the cell actually divides into two identical, functional cells.
The cell cycle and the relationship of antitumor drug action to the cycle
Classification of cytotoxic drugs (based on cell cycle)

Cell cycle non specific drugs effective in dividing and dormant cells Cell cycle specific drugs effective in dividing cells Tissue specific agents certain tumours require certain hormones - hormone antagonists - reduce hormone secretion at the pituitary gland miscellaneous agents
Cell cycle non specific drugs

Alkylating agents
cross links in DNA nitrogen mustards, lomustine, carmustine, hexamethylmelamine & cyclophosphamide,etc. Cytotoxic antibiotic agents too toxic to be used as antibiotics Anthracyclines: doxyrubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone; - Mitomycin & dactinomycin,
Cytotoxic antiviral agents

Fludarabine, inhibits DNA synthesis
Camptothecins (irinotecan, topotecan) Platinum analogs (carboplatin, cisplatin, oxaliplatin)

Cell cycle specific drugs

Antimetabolites
Capecitabine, Cladribine, Fludarabine, Fluorouracil, Gemcitabin, Mercaptopurine, Methotrexate, Thioguanine
Antibiotic: - Bleomycin Epipodophyllotoxins : - Etoposide, Teniposide Taxane: - Docetaxel, Paclitaxel Vinca alkaloid :- Vicristine, Vinblastine, Vinorelbine
Cell cycle specific drugs cont. S phase inhibitors

insert into DNA during replication, causing misreading or fracture - cytarabine, fluorouracil, mercaptopurine, methotrexate
Mitotic poisons
alkaloids from the periwinkle plant (Vinca rosea) prevent formation of mitotic spindle fibres vincristine, vinblastine Taxanes alkaloids from the Yew tree (Taxus bervifolia) stabilise microtubules preventing reorganisation for mitosis paclitaxel, docetaxel
Tissue specific agents

Hormonal antagonists endometrial & breast cancers medroxyprogesterone, tamoxifen prostate cancers flutamide, fosfestrol Disruption of pituitary function leuprolein & goserelin reduce secretion of gonadotrophic hormones prostate cancer
Miscellaneous antitumor agents

Aminoglutethimide
interferes with steroid hormone synthesis
metastasising breast & prostate cancers
Interferon alpha 2 a & 2 b

enhance cytotoxic immune cell responsiveness
L-asparaginase (colaspase)
from bacteria stops synthesis of asparagine aa essential in cell division some cancer cells cannot make it and must get it from blood, this drug destroys it in blood
Tretinoin
reduce proliferation of leukaemia cells
Principles of tumour therapy

Broadly, most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells they are termed cytotoxic. Some drugs cause cells to undergo apoptosis (so-called "cell suicide").
Principles of tumour therapy (cont.)

As chemotherapy affects cell division, tumours with high growth fractions (such as acute myelogenous leukemia and the lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time. This means that other fast dividing cells such as those responsible for hair growth and for replacement of the intestinal epithelium (lining), BM are also affected. However, some drugs have a better side-effect profile than others, enabling doctors to adjust treatment regimens to the advantage of patients in certain situations.
Principles of tumour therapy (cont.)

Chemotherapeutic drugs affect "younger" tumours (i.e. less differentiated) more effectively, because at a higher grade of differentiation, the propensity to growth usually decreases. Near the center of some solid tumours, cell division has effectively ceased, making them insensitive to chemotherapy. Another problem with solid tumours is the fact that the chemotherapeutic agent often does not reach the core of the tumour. Solutions to this problem include radiation therapy (both brachytherapy and teletherapy) and surgery.
TREATING CANCER
Treatment methods:
Surgery Radiation Chemotherapy (drugs) Different cancers respond to different treatments Importance of cell cycle kinetics Importance of neoplastic cell burden reside eg. the CNS, testes
Depending on the drug chosen, chemotherapy will affect malignant cells in one of three ways: Damage the DNA of the cancer cells, so they can no longer reproduce.
This is done by altering the DNA structure in the nucleus of the cell preventing replication.
During the S phase of cell life, inhibit the synthesis of new DNA strands, so that no cell replication is possible.
This occurs when the drugs block the formation of nucleotides that are necessary for new DNA to be created.
Stop the mitotic processes of the cell, so that the cancer cell cannot divide into two cells.
The formation of mitotic spindles is necessary to move the original DNA and the replicated DNA to opposite sides of the cell so the cell can divide into two cells.
Problems with chemotherapy Toxicity to normal cells

dose limiting we don t have cancer specific drugs high growth fraction human cells affected bone marrow, GIT epithelium, hair follicles germinal epithelium of testes
Cure requires 100% kill rate Failure of early detection

early detection is rare and difficult
Problems with chemotherapy cont.

Solid tumours respond poorly
low growth fraction Drug resistance p-glycoprotein pumps drug out of cell
Heterogeneity of cancer cells

Limited drug access to tumour cells
Therapeutic strategies
Intermittent chemotherapy
BM recovery
Combination therapy attack different mechanisms reduce side effects - reduce injury to normal cells suppress drug resistance Optimising dosage schedules Regional drug delivery intra arterial, intrathecal, etc
Antineoplastic agents/cytotoxic drugs

The majority of chemotherapeutic drugs can be divided in to: Alkylating agents, Antimetabolites, Anthracyclines, Plant alkaloids, Topoisomerase inhibitors, and others antitumour agents. All of these drugs affect cell division or DNA synthesis and function in some way.
Antineoplastic agents/cytotoxic drugs (cont.)
Some newer agents don't directly interfere with DNA. These include the new tyrosine kinase inhibitor imatinib mesylate (Gleevec or Glivec), which directly targets a molecular abnormality in certain types of cancer (chronic myelogenous leukemia, gastrointestinal stromal tumors). In addition, some drugs may be used which modulate tumor cell behaviour without directly attacking those cells. Hormone treatments fall into this category of adjuvant therapies.
Antineoplastic agents/cytotoxic drugs (cont.)
Monoclonal antibodies:
Alemtuzumab, Bevacizumab, Cetuximab, Gemtuzumab, Panitumumab, Rituximab, Trastuzumab
Photosensitizer:
Aminolevulinic acid, Methyl aminolevulinate, Porfimer sodium, Verteporfin
Other:
Alitretinoin, Altretamine, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Bexarotene, Bortezomib, Dasatinib, Denileukin diftitox, Erlotinib, Estramustine, Gefitinib, Hydroxycarbamide, Imatinib, Pentostatin, Masoprocol, Mitotane, Pegaspargase
ALKYLATING AGENTS
Are drugs that work by directly attacking the DNA of a cell. These drugs can work at any time of the cell cycle, but are most effective during DNA synthesis. They are used to treat Hodgkin's disease, lymphomas, chronic leukemias, and certain carcinomas of the lung, breast, prostrate, and ovary. Alkylating agents are administered either orally or intravenously. Examples of drugs in this category are Cyclophosphamide and Mechlorethamine, Cisplatin (Platinol).
Alkylating agents cont.

Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells.
Nitrogen mustards
: Chlorambucil, Chlormethine, Cyclophosphamide,Ifosfamide, Melphalan.
Nitrosoureas Platinum
: Carmustine, Fotemustine, Lomustine, Streptozocin. : Carboplatin, Cisplatin, Oxaliplatin, BBR3464.
Busulfan, Dacarbazine, Mechlorethamine, Procarbazine,
Temozolomide, ThioTEPA, Uramustine

Alkylating agents cont.

NITROSOUREAS
are similar to alkylating agents, and work by inhibiting the changes necessary for DNA repair. A very important feature of this class of drugs is that they can cross the blood-brain barrier which makes them very useful for treating brain tumors. They can also be used to treat lymphomas and melanomas. Nitrosoureas are administered either orally or intravenously. Examples of drugs in this category are Carmustine and Lomustine.
DNADNADNA DNA
Mechanism of action of alkylating agents

Nitrogen mustards employed in therapy (alkilating agents)

Metabolism of cyclophosphamide M M M M
Antimetabolites
Anti-metabolites masquerade as purine (azathioprine, mercaptopurine) or pyrimidine - which become the building blocks of DNA.
They prevent these substances becoming
incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division
They also affect RNA synthesis. Due to their efficiency, these drugs are the most widely used cytostatics.
ANTIMETABOLITES cont.
They block cell growth by interfering with DNA synthesis. These drugs work by mimicking a substance involved in DNA synthesis, inhibiting production of an acid necessary for DNA to be synthesized. These drugs affect the "S" phase of the cell cycle. Antimetabolites are used to treat tumors of the gastrointestinal tract, breast, and ovary. They are administered either orally or intravenously.
Antimetabolite (cont.)
Folic acid : Methotrexate, Pemetrexed, Raltitrexed. Purine : Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Tioguanine. Pyrimidine : Capecitabine. Cytarabine, Fluorouracil, Gemcitabine
The strucure-activity bases for antifolate action

Structures of available pyrimidine analogs

Site of action of 5-fluoro-2-deoxyuridine-5phosphate (5-FdUMP) Other action of 5-FU nucleotides: - Inhibition of RNA processing - Incorporation into DNA
Mechanisms of tumor cell resistance to methotrexate

PLANT(VINCA) ALKALOIDS
Work by preventing cell division. During metaphase, mitotic spindles hold the two sets of DNA the cell needs to divide. The spindles are formed using a protein called tubulin. Plant alkaloids bind to tubulin, which prevents the formation of mitotic spindles. Without mitotic spindles, the cell cannot divide. These drugs are derived from plants and are used to treat Wilm's tumor, and cancers of the lung, breast, and testes. Plant alkaloids are administered intravenously. Some examples of this category are Vincristine and Vinblastine.
Plant alkaloid antitumor

Plant alkaloids and terpenoids These alkaloids are derived from plants and block cell division by preventing microtubule function. Microtubules are vital for cell division and without them it can not occur. The main examples are:
vinca alkaloids : Vinblastine, Vincristine, Vindesine, Vinorelbine Taxanes : Docetaxel, Paclitaxel.
Vinca alkaloids
Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phase of the cell cycle). They are derived from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). The vinca alkaloids include: Vincristine, Vinblastine, Vinorelbine Vindesine
Podophyllotoxin
Podophyllotoxin is a plant-derived compound used to produce two other cytostatic drugs, etoposide and teniposide. They prevent the cell from entering the G1 phase (the start of DNA replication) and the replication of DNA (the S phase). The exact mechanism of its action still has to be elucidated. The substance has been primarily obtained from the American Mayapple (Podophyllum peltatum). Recently it has been discovered that a rare Himalayan Mayapple (Podophyllum hexandrum) contains it in a much greater quantity, but as the plant is endangered, its supply is limited. Studies have been conducted to isolate the genes involved in the substance's production, so that it could be obtained recombinantively.
Taxanes
Taxanes are derived from the Yew Tree. Paclitaxel is derived from the bark of the European Yew Tree (Cemara) while Docetaxel is derived from the pine needle of the Pacific Yew Tree. Taxanes enhance stability of microtubules, preventing the separation of chromosomes during anaphase. Taxanes include: Paclitaxel, Docetaxel
Topoisomerase inhibitors
Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling. Some type I topoisomerase inhibitors include camptothecins: irinotecan and topotecan. Examples of type II inhibitors include amsacrine, etoposide, etoposide phosphate, and teniposide. These are semisynthetic derivatives of epipodophyllotoxins, alkaloids naturally occurring in the root of mayapple (Podophyllum peltatum).
ANTITUMOR ANTIBIOTICS
They work by binding with DNA to prevent RNA synthesis. These drugs also prevent cell growth by preventing DNA replication. Antitumor antibiotics prevent the DNA from reattaching itself together which causes the cell to die. This category of drugs is used to treat a wide variety of cancers including testicular cancer and leukemia. Antitumor antibiotic drugs are administered intravenously
Antitumour antibiotics cont.

The most important immunosuppressant from this group is dactinomycin, which is used in kidney transplantations. Cytotoxic/antitumor antibiotics: Anthracycline family: Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Valrubicin. Bleomycin, Hydroxyurea, Mitomycin
Antitumour antibiotics cont.

Four major mechanism Anthracyclines : 1. Inhibition of topoisomerase II 2. High affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA, RNA, and DNA strand scission 3. Binding to cellular membranes to alter fluidity and ion transport 4. Generation of semiquinone free radicals and oxygen free radicals through an enzyme-mediated reductive process cause of the drugs cardiac toxicity
Hormonal therapy
Several malignancies respond to hormonal therapy. Strictly speaking, this is not chemotherapy. Cancer arising from certain tissues, including the mammary and prostate glands, may be inhibited or stimulated by appropriate changes in hormone balance. Some other tumours are also hormone dependent, although the specific mechanism is still unclear
Hormonal therapy
Steroids (often dexamethasone) can inhibit tumour growth or the associated edema (tissue swelling), and may cause regression of lymph node malignancies. Prostate cancer is often sensitive to finasteride, an agent that blocks the peripheral conversion of testosterone to dihydrotestosterone. Breast cancer cells often highly express the estrogen and/or progesterone receptor. Inhibiting the production (with aromatase inhibitors) or action (with tamoxifen) of these hormones can often be used as an adjunct to therapy. Gonadotropin-releasing hormone agonists (GnRH), such as goserelin possess a paradoxic negative feedback effect followed by inhibition of the release of FSH (folliclestimulating hormone) and LH (luteinizing hormone), when given continuously.
STEROID HORMONES cont

These drugs modify the growth of hormone dependant cancers. They induce a change in the three dimensional shape of the receptor on a cell, preventing the cell's binding to the needed estrogen response element on the DNA. These drugs are most commonly used in treating breast cancer. The hormones are administered orally. Some examples of this category are Tamoxifen and Flutamide.
Summary of the mechanisms and sites of action of chemotherapeutic agents useful in neoplastic disease
Other uses of cytostatic chemotherapy agents (including the ones mentioned below) are: the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, the treatment of some chronic viral infections such as Hepatitis, and the suppression of transplant rejections
Treatment schemes
There are a number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms. Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiation therapy or surgery. Most cancers are now treated in this way. Combination chemotherapy is a similar practice which involves treating a patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects. The biggest advantage is minimising the chances of resistance developing to any one agent.
Treatment schemes cont.

Most chemotherapy regimens require that the patient is capable to undergo the treatment. Performance status is often used as a measure to determine whether a patient can receive chemotherapy, or whether dose reduction is required. - Tumour marker identity - Organ functions test
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Type of chemotherapy
neoadjuvant chemotherapy (preoperative treatment) initial
chemotherapy is aimed for shrinking the primary tumour, thereby rendering local therapy (surgery or radiotherapy) less destructive or more effective. Adjuvant chemotherapy (postoperative treatment) can be used when there is little evidence of cancer present, but there is risk of recurrence. This can help reduce chances of resistance developing if the tumour does develop. It is also useful in killing any cancerous cells which have spread to other parts of the body. This is often effective as the newly growing tumours are fastdividing, and therefore very susceptible.
Type of chemotherapy cont

Palliative chemotherapy is given without curative intent,
but simply to decrease tumor load, to lessen a patients cancer symptoms, and increase life expectancy. For these regimens, a better toxicity profile is generally expected.
Biological agents affect natural processes that may

stimulate cancer cell growth and survival
Radiosensitizing chemotherapy given in conjunction

with radiation therapy, intended to boost the anticancer effects of radiation therapy
Signal transduction inhibitors are given to disrupt

abnormal process present within cancer cells and are necessary for the growth or survival of cancer cells
Type of chemotherapy cont

Immunotherapy is intended to boost the recognition of
cancer cells by the bodys immune system,thereby helping the body to kill cancer cells
Cellular therapy involves the use of immunologic cells that

selectively destroy cancer cells
Radiopharmaceuticals - are substance that have been
marked with radioative markers to selectively deliver radiation therapy to cancer cells
Anticancer antibodies are specially engineered antibodies

given with goal of selectively targeting cancer cells for removal by the immune system
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Type of chemotherapy cont.

Anticancer vaccine, contain agent intended to help the
immune system more readily recognize cancer cells as foreign (and thus attack them)
Anticancer viral therapy, involve giving viruses to

patients with the hope that the virus will selectively kill cancer cells.
Gene therapy, introduce DNA/genetic material into cancer

cells in hopes of either restoring them to normal or killing them
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Side-effects of cytotoxic drugs

The treatment can be physically exhausting for the patient. Current chemotherapeutic techniques have a range of side effects mainly affecting the fast-dividing cells of the body. Important common side-effects include (dependent on the agent):
Hair loss , alopecia, Nausea and vomiting Diarrhea or constipation , Anemia Depression of the immune system hence (potentially lethal) infections and sepsis Hemorrhage , Secondary neoplasms Cardiotoxicity Hepatotoxicity, reproductive toxicity Nephrotoxicity , Ototoxicity
Other Side-effects of cytotoxic drugs

In particularly large tumors, such as large lymphomas, some patients develop tumor lysis syndrome from the rapid breakdown of malignant cells. Although prophylaxis is available and is often initiated in patients with large tumors, this is a dangerous side-effect which can lead to death if left untreated. A proportion of patients reports fatigue or non-specific neurocognitive problems, such an inability to concentrate; this is colloquially referred to as "chemo brain" by patients' groups Chemotherapy may increase the risk of cardiovascular disease and occasionally leads to secondary cancer. Hyperuricaemia high uric acid levels DNA breakdown product kidney injury need anti gout drugs Carcinogenesis May take years to appear
anti nausea & vomiting

Approved 5-HT3 inhibitors include: dolasetron (Anzemet), granisetron (Kytril), and ondansetron (Zofran). The newest 5-HT3 inhibitor, Aloxi (palonosetron), has a distinct advantage over the other 5-HT3 inhibitors because, in addition to preventing acute nausea and vomiting, Aloxi also prevents delayed nausea and vomiting, which occurs during the 2-5 days after treatment. Aloxi is the only drug in its class that is approved by the FDA for the treatment of delayed nausea and vomiting. Some studies and patient groups claim that the use of cannabinoids derived from marijuana during chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat. Some synthetic derivatives of the active substance in marijuana (tetrahydrocannabinol or THC) such as Marinol may be practical for this application.
Immunotherapy
Immunotherapy has been used as adjunct to traditional treatments. Both active and passive means of stimulating the nonspecific and specific immune systems have been employed, in some cases with significant success (Table 1).
Immunity against tumors

Evidence for immunity against malignancy comes mostly from experimental tumors, although there is ample evidence for antitumor immune reactivity in humans. In experimental studies, animals can be immunized by administering inactivated tumor cells or by removal of a primary tumor. Also, immunity can be transferred from an animal, in which a tumor has regressed, to a naive animal by injection of lymphocytes (T cells). All components of the immune system (non-specific and specific; humoral and cellular) can affect the growth and progression of a tumor.
Escape from immuno-surveillance

A number of mechanisms have been suggested for the escape of malignant cells from host immunosurveillance. Tumors may not express neo-antigens that are immunogenic or they may fail to express costimulatory molecules for the activation of T-cells. In addition, certain tumors are known to lack or be poor expressers of MHC antigen.
Escape from immuno-surveillance (cont.)

Another reason for failure of immunosurveillance may be the fact that in the early development of a tumor, the amount of antigen may be too small to stimulate the immune system and, due to the rapid proliferation of malignant cells, the immune system is quickly overwhelmed. In addition, some tumors may evade the immune system by secreting immunosuppressive molecules and others may induce suppressor cells. Also, some tumors may shed their unique antigens which block antibodies and T cells from reacting with malignant cells.
Tumor associated antigens

In animals, most chemically- or physically- induced tumors or or those produced as a result of a virus, have neo-antigens
onco-fetal antigens - Onco-fetal antigens may appear due to de-repression of genes

that were only expressed early in life. - Two major onco-fetal antigens are: alpha-fetoprotein (AFP) and carcino-embryonic antigen (CEA ). - AFP is produced only as a secreted protein - whereas CEA is found both on cell membranes and in secreted fluids.
Tumor associated antigens (cont.) Alpha-fetoprotein

The normal range of AFP concentrations in humans is 0-20 ng/ml. This level rises considerably in patients with hepatomas and nonseminal testicular carcinoma. A 5-fold or higher rise in this protein is used for monitoring hepatomas and testicular cancers. AFP level may also be raised in some non-malignant conditions, such as cirrhosis, in hepatitis and other forms of liver damage.
Carcinoembryonic antigen
CEA levels in normal people range up to 2.5 ng/ml, but they increase significantly in certain malignancies, particularly colo-rectal cancers. - They may also rise in some non-malignant conditions (such as
chronic cirrhosis, pulmonary emphysema and heavy smoking). - Levels that are 4-5 times normal have been used to predict recurrence of colo-rectal tumors.
Tumor associated antigens (cont.)

Tumor associated transplantation antigens (TATA) on viral tumors
A number of viruses cause different types of tumors in animals (SV40 virus, adenovirus, Rous sarcoma virus, Friend erythroleukemic virus, Moloney Rauscher and Gross viruses). Viruses are involved or suspected to be involved in some human malignancies (HTLV-1 in leukemia, hepatitis-B virus in hepatic carcinoma, papilloma virus in cervical cancer). Virus-induced tumors express cell surface antigens (distinct from antigens of the virion itself) which are shared by all tumors induced by the same virus. These antigens are characteristic of the tumor-inducing virus, regardless of tissue origin of the tumor or animal species in which the tumor exists
Tumor associated antigens (cont.)
Tumor associated transplantation antigens on chemically-induced tumors

Chemically-induced tumors are different from virally-induced tumors in that they are extremely heterogeneous in their antigenic characteristics. Thus, any two tumors induced by the same chemical, even in the same animal, rarely share common tumor specific antigens These unique antigens on chemically-induced tumors are referred to as tumor specific transplantation antigens (TSTA).
Immunotherapy
A variety of immunopotentiating agents (biological response modifiers) are used to enhance anti-tumor immunity. They include bacterial products, synthetic chemicals and cytokines (Table 2). Most of these agents exert their effects by activating macrophages and natural killer (NK) cells, eliciting cytokines or enhancing Tcell functions. A number of cytokines have been used to potentiate the immune function of the host since the discovery that these cytokines have potent and selective effects on certain components of the immune system (Table 3).
Immunotherapy
Monoclonal anti-tumor antibodies have been used in different forms for the treatment of cancer, either because of their direct effect or as vehicles to target anticancer drugs, toxins and the non-specific components of the host's immune system to the site of tumor In addition, such specific antibodies are also used in the diagnosis of metastatic lesions, otherwise not detectable by conventional radiologic means.
Table 1. Immunotherapy of tumors

nonspecific BCG, Propionibacterium acnes, levamisole, cytokine genes, etc. killed tumor cells or their extract, recombinant antigens, idiotype, costimulatory molecule genes, etc. LAK cells, cytokines Antibodies alone or coupled to drugs, prodrug toxins or radioisotope; bispecific antibodies; T-cells LAK cells and bispecific antibody
Active
specific Nonspecific Passive specific Combined
* BCG: Bacillus Calmette Geurin is a bovine strain of Mycobacterium tuberculosis

Table 2. Non-specific active immunotherapy: biological response modifiers (BRMs)

Type of BRM bacterial product Examples BCG, P. acnes, muramyl di-peptide, trehalose dimycolate pyran, poly I:C, pyrimidines interferon-alpha, beta, -gamma, IL-2, TNF Major effect activate macrophages and NK cells (via cytokines) induce interferon production activate macrophages and NK cells
synthetic molecules Cytokines
Table 3. Cytokine therapy of tumors

Cytokine IFNalpha, beta IFNgamma IL-2 Tumor type and result remission of hairy cell leukemia, weak effect on some carcinomas remission of peritoneal carcinoma of ovary: ineffective systemically Anti-tumor mechanism(s) increased expression of class I MHC, possible cytostatic anti-tumor effect, increased MHC antigens; macrophage, Tc and NK cell activation
remission in renal T-cell proliferation and activation, carcinoma and melanoma NK cells activation can reduce malignant ascites macrophage and lymphocyte activation
TNFalpha
IMMUNOMODULATORS
Immunostimulant Substances that stimulate immunity Antisera antibodies from another source antivenom transient but instant protection Vaccines whole or part if infectious bacteria/virus develop our own immunity Cytokines interferon etc
IMMUNOMODULATORS cont.
Immunosuppressants Tolerogen
Sel imun tetap Aktif, tetapi tiak responsif thd antigen autoimun diseases
Prevent rejection of transplants Treat autoimmune disease CORTICOSTEROIDS depress t-cells, antibody production & macrophage responsiveness CYCLOSPORIN blocks t-cell proliferation AZATHIOPRINE suppress all immune cell proliferation

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CANCER CHEMOTHERAPY (Antineoplasia, Cytotoxic drugs)

Maria Immaculata Iwo SEKOLAH FARMASI ITB

cause metabolic abnormalities illness and eventual death

maria immaculata iwo, school of pharmacy itb 5

 The cell cycle

Classification of cytotoxic drugs (based on cell cycle)

Cell cycle non specific drugs

Cytotoxic antiviral agents

Camptothecins (irinotecan, topotecan) Platinum analogs (carboplatin, cisplatin, oxaliplatin)

Cell cycle specific drugs

Capecitabine, Cladribine, Fludarabine, Fluorouracil, Gemcitabin, Mercaptopurine, Methotrexate, Thioguanine

Cell cycle specific drugs cont. S phase inhibitors

Tissue specific agents

Miscellaneous antitumor agents

metastasising breast & prostate cancers

Interferon alpha 2 a & 2 b

Principles of tumour therapy

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Principles of tumour therapy (cont.)

Principles of tumour therapy (cont.)

Problems with chemotherapy Toxicity to normal cells

Cure requires 100% kill rate Failure of early detection

Problems with chemotherapy cont.

Heterogeneity of cancer cells

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Antineoplastic agents/cytotoxic drugs

Antineoplastic agents/cytotoxic drugs (cont.)

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Antineoplastic agents/cytotoxic drugs (cont.)

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Alkylating agents cont.

: Chlorambucil, Chlormethine, Cyclophosphamide,Ifosfamide, Melphalan.

: Carmustine, Fotemustine, Lomustine, Streptozocin. : Carboplatin, Cisplatin, Oxaliplatin, BBR3464.

 Busulfan, Dacarbazine, Mechlorethamine, Procarbazine,

Temozolomide, ThioTEPA, Uramustine

Alkylating agents cont.

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Mechanism of action of alkylating agents

Nitrogen mustards employed in therapy (alkilating agents)

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They prevent these substances becoming

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The strucure-activity bases for antifolate action

Structures of available pyrimidine analogs

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Mechanisms of tumor cell resistance to methotrexate

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Plant alkaloid antitumor

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Antitumour antibiotics cont.

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Antitumour antibiotics cont.

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STEROID HORMONES cont

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Treatment schemes cont.

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The cell cycle

Busulfan, Dacarbazine, Mechlorethamine, Procarbazine,