Antineoplastic Agents 2010 Dental MARCH.ppt
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Transcript of Antineoplastic Agents 2010 Dental MARCH.ppt
Pharmacology of Antineoplastic Agents
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Outline of Lecture Topics:
1. Background2. Antineoplastic Agents: classification
a. Cell Cycle Specific (CCS) agentsb. Cell Cycle Non-Specific (CCNS) agentsc. Miscellaneous (e.g., antibodies) agents
4. Mechanisms of action5. Side Effects6. Drug Resistance
Kishore Wary, Ph.D.Dept [email protected]
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PART I
1. Background
2. Antineoplastic Agents
a. Cell Cycle Specific (CCS) agentsb. Cell Cycle Non-Specific (CCNS) agentsc. Miscellaneous (e.g., antibodies) agents
Cancer
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Definition:Cancer* is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems, this process is called metastasis.
Categorized based on the functions/locations of the cells from which they originate:
1.Carcinoma - skin or in tissues that line or cover internal organs. E.g., Epithelial cells. 80-90% reported cancer cases are carcinomas.2.Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. 3.Leukemia - White blood cells and their precursor cells such as the bone marrow cells, causes large numbers of abnormal blood cells to be produced and enter the blood. 4.Lymphoma - cells of the immune system that affects lymphatic system.5.Myeloma - B-cells that produce antibodies- spreads through lymphatic system.6.Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord.
(*National Cancer Institute, NCI)
Cancer Therapeutic Modalities (classical)
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1. Surgery
2. Radiation
3. Chemotherapy
1/3 of patients without metastasis Respond to surgery and radiation.
If diagnosed at early stage, close to 50% cancer could be cured.
50% patients will undergo chemotherapy,to remove micrometastasis. However,chemotherapy is able to cure only about 10-15% of all cancer patients.
Cancer ChemotherapyChapter 55. B.G. Katzung
5Cancer ChemotherapyChapter 55. B.G. Katzung
New types of cancer treatment
Hormonal Treatments: These drugs are designed to prevent cancer cell growth by preventing the cells from receiving signals necessary for their continued growth and division. E.g., Breast cancer – tamoxifen after surgery and radiation
Specific Inhibitors: Drugs targeting specific proteins and processes that are limited primarily to cancer cells or that are much more prevalent in cancer cells.
Antibodies: The antibodies used in the treatment of cancer have been manufactured for use as drugs. E.g., Herceptin, avastin
Biological Response Modifiers: The use of naturally occuring, normal proteins to stimulate the body's own defenses against cancer. E.g., Abciximab, rituxmab
Vaccines: Stimulate the body's defenses against cancer. Vaccines usually contain proteins found on or produced by cancer cells. By administering these proteins, the treatment aims to increase the response of the body against the cancer cells.
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Cancer Chemotherapy (Background)A. Most of the recent progress using antineoplastic therapy is based on:
1. Development of new combination therapy of using existing drugs.2. Better understanding of the mechanisms of antitumor activity.3. Development of chemotherpeutic approaches to destroying
micrometastases4. Understanding the molecular mechanisms concerning the initiation of
tumor growth and metastasis.5. Recognition of the heterogeneity of tumors
B. Recently developed principles which have helped guide the treatment of neoplastic disease
1. A single clonogenic cell can produce enough progeny to kill the host.
2. Unless few malignant cells are present, host immune mechanisms do not play a significant role in therapy of neoplastic disease.
3. A given therapy results in destruction of a constant percentage as opposed to a constant number of cells, therefore, cell kill follows first order kinetics.
Cancer Chemotherapy
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C. Malignancies which respond favorably to chemotherapy:
1. choriocarcinoma, 2. Acute leukemia,3. Hodgkin's disease,4. Burkitt's lymphoma, 5. Wilms' tumor,6. Testicular carcinoma,7. Ewing's sarcoma, 8. Retinoblastoma in children, 9. Diffuse histiocytic lymphoma and10.Rhabdomyosarcoma.
D. Antineoplastic drugs are most effective against rapidly dividing tumor cells.
E. The Main Goal of Antineoplastic Agents
IS to eliminate the cancer cells without affecting normal tissues (the concept of differential sensitivity). In reality, all cytotoxic drugs affect normal tissues as well as malignancies - aim for a favorable therapeutic index (aka therapeutic ratio).
Therapeutic Index =LD50
-----ED50
A therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50).
Cancer ChemotherapyChapter 55. B.G. Katzung
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Infrequent scheduling oftreatment courses.Prolongs survival but does not cure.
More intensive and frequent treatment.Kill rate > growth rate.
Untreated patients
F. The effects of tumor burden, scheduling, dosing, and initiation/duration of treatment on patient survival.
Early surgical removal of the primary tumor decreases the tumor burden. Chemotherapy will remove persistant secondary tumors.
Cancer ChemotherapyChapter 55. B.G. Katzung
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General rules of chemotherapy
Aggressive high-dose chemotherapy•Dose- limiting is toxicity towards normal cells•Cyclic regimens - repeated administrations with appropriate intervals for regeneration of normal cells (e.g., bone marrow cells) •Supportive therapy - to reduce toxicity
hematotoxicity – bone marrow transplantation, hematopoietic growth factors Specific antagonists: antifolate (methotrexate) – folate (leucovorin)MESNA - donor of –SH groups, decreased urotoxicity of cyclophosphamide. Detoxifying agent. dexrazoxane: chelates iron, reduced anthracycline cardiotoxicityamifostine: reduces hematotoxicity, ototoxicity and neurotoxicity of alkylating agents
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General rules of chemotherapy
•Combination of several drugs with different mechanisms of action, different resistance mechanisms, different dose-limiting toxicities.
•Adjuvant therapy: Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.
•Neoadjuvant therapy: Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery, is given. Examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy. It is a type of induction therapy.
Cancer ChemotherapyChapter 55. B.G. Katzung
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General rules of chemotherapy
•Supportive therapy: -Antiemetics (5-HT3 -antagonists)
-Antibiotic prophylaxis and therapy (febrile neutropenia)-Prophylaxis of urate nephropathy (allopurinol)-Enteral and parenteral nutrition-Pain – analgesic drugs-Psychological support
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Alkylating agentsTopoisomerase inhibitors Antimetabolites
Molecularly targeted
busulfan dactinomycin cytarabine erlotinibcarboplatin daunomycin clofarabine imatinibcarmustine doxorubicin fludarabine sorafenibcisplatin etoposide gemcitabine sunitinibcyclophosphamide etoposide phosphate mercaptopurine tretinoindacarbazine idarubicin methotrexate Herceptinifosfamide irinotecan nelarabine Miscellaneouslomustine liposomal daunomycin thioguanine arsenic trioxidemechlorethamine liposomal doxorubicin Tubulin binders asparaginasemelphalan mitoxantrone docetaxel bleomycinoxaliplatin teniposide ixabepilone dexamethasoneprocarbazine topotecan vinblastine hydroxyureatemozolomide vincristine mitotane
thiotepa vinorelbine PEG-asparaginase
paclitaxel prednisone
Antineoplastic Agents
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Chemotherapy: classification based on the mechanism of action
Antimetabolites: Drugs that interfere with the formation of key biomolecules including nucleotides, the building blocks of DNA.
Genotoxic Drugs: Drugs that alkylate or intercalate the DNA causing the loss of its function.
Plant-derived inhibitors of mitosis: These agents prevent proper cell division by interfering with the cytoskeletal components that enable the cell to divide.
Plant-derived topoisomerase inhibitors: Topoisomerases unwind or religate DNA during replication.
Other Chemotherapy Agents: These agents inhibit cell division by mechanisms that are not covered in the categories listed above.
15Cancer ChemotherapyChapter 55. B.G. Katzung
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G0 = resting phaseG1 = pre-replicative phaseG2 = post-replicative phaseS = DNA synthesisM = mitosis or cell division
M
S
G G2 1 Hydrocortisone
Vincristine,Vinblastine
G0
CyclophosphamideBleomycinActinomycin D
Actinomycin D5-Fluorouracil
Cytosine arabinosideMethotrexate6-Mercaptopurine6-Thioguanine
Purine antagonistsMethotrexateCyclophosphamide5-Fluorouracil
Cytosine arabinosideDaunomycin
Paclitaxel, Docetaxel
resting
Cell cycle specificity of Anti-Neoplastic Agents
17Cancer ChemotherapyChapter 55. B.G. Katzung
PART II
4. Mechanisms of action5. Side Effects6. Drug Resistance
Pharmacology of Antineoplastic Agents
18Cancer ChemotherapyChapter 55. B.G. Katzung
DNA
RNA
Proteintubulin
Purines andPyrimidines
Asparaginase
Tubulin binders
Alkylating agentsTopoisomerase Inh.
Antimetabolites
Chemotherapy: Mechanisms of Action
1
Major Clinically Useful Alkylating Agents
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Bis(mechloroethyl)amines Nitrosoureas Aziridines
Cancer ChemotherapyChapter 55. B.G. Katzung
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H2N
O
N
N
HN
N
HO
O
OP
O
NH2
O
N
N NH
N
OOP
OHO
NR
Crosslinking: Joining two or more molecules by a covalent bond. This can either occur in the same strand (intrastrand crosslink) or in the opposite strands of the DNA (interstrand crosslink). Crosslinks also occur between DNA and protein. DNA replication is blocked by crosslinks, which causes replication arrest and cell death if the crosslink is not repaired.
An Example of DNA Crosslinking
21Cancer ChemotherapyChapter 55. B.G. Katzung
Alkylating Agents (Covalent DNA binding drugs)
1. The first class of chemotherapy agents used.
2. They stop tumour growth by cross-linking guanine nucleobases in DNA double-helix strands - directly attacking DNA.
3. This makes the strands unable to uncoil and separate.
4. As this is necessary in DNA replication, the cells can no longer divide.
5. Cell-cycle nonspecific effect6. Alkylating agents are also
mutagenic and carcinogenic
AT
C G
CG
GAT
G C
E.g., Mechlorethamine (Nitrogen Mustards)
22Cancer ChemotherapyChapter 55. B.G. Katzung
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Cyclophosphamide
Cyclophosphamide is an alkylating agent. It is a widely used as a DNA crosslinking and cytotoxic chemotherapeutic agent.
•It is given orally as well as intravenously with efficacy.
•It is inactive in parent form, and must be activated to cytotoxic form by liver CYT450 liver microsomaal system to 4-Hydroxycyclophamide and Aldophosphamide.
•4-Hydroxycyclophamide and Aldophosphamide are delivered to the dividing normal and tumor cells.
•Aldophosphamide is converted into acrolein and phosphoramide mustard.
•They crosslink DNAs resulting in inhibition of DNA synthesis
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Cyclophosphamide Metabolism
Inactive
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Cyclophosphamide
Clinical Applications:
1. Breast Cancer2. Ovarian Cancer3. Non-Hodgkin’s Lymphoma 4. Chronic Lymphocytic Leukemia (CLL)5. Soft tissue sarcoma6. Neuroblastoma7. Wilms’ tumor8. Rhabdomyosarcoma
Cancer ChemotherapyChapter 55. B.G. Katzung
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Cyclophosphamide
Major Side effects
1. Nausea and vomiting 2. Decrease in PBL count 3. Depression of blood cell counts 4. Bleeding5. Alopecia (hair loss)6. Skin pigmentation7. Pulmonary fibrosis
Cancer ChemotherapyChapter 55. B.G. Katzung
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IfosphamideMechanisms of ActionSimilar to cyclophosphamideApplication 1.Germ cell cancer, 2.Cervical carcinoma, 3.Lung cancer4.Hodgkins and non-Hodgkins lymphoma5.Sarcomas
Major Side EffectsSimilar to cyclophosphamide
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1. Mechanism of Action
2. Clinical application 3. Route 4. Side effects
a. Nitrogen Mustards
A. Mechlorethamine DNA cross-links, resulting in inhibition of DNA synthesis and function
Hodgkin’s and non-Hodgkin’s lymphoma
Must be given Orally
Nausea and vomiting, decrease inPBL count, BM depression, bleeding, alopecia, skin pigmentation, pulmonary fibrosis
B. Cyclophosphamide Same as above Breast, ovarian, CLL, soft tissue sarcoma, WT, neuroblastoma
Orally and I.V. Same as above
C. Chlorambucil Same as above Chronic lymphocytic leukemia
Orally effective Same as above
D. Melphalan Same as above Multiple myeloma, breast, ovarian
Orally effective Same as above
E. Ifosfamide Same as above Germ cell cancer, cervical carcinoma, lung, Hodgkins and non-Hodgkins lymphoma, sarcomas
Orally effective Same as above
A. Alkylating agents
Cancer ChemotherapyChapter 55. B.G. Katzung
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1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
b. Alkyl Sulfonates
A. Busulfan Atypical alkylating agent. Chronic granulocytic leukemia
Orally effective Bone marrow depression, pulmonary fibrosis, and hyperuricemia
c. Nitrosoureas 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
A. Carmustine DNA damage, it cancross blood-brain barrier
Hodgkins and non-Hodgkins lymphoma, brain tumors, G.I. carcinoma
Given I.V. must be given slowly.
Bone marrow depression,CNS depression, renal toxicity
B. Lomustine Lomustine alkylates and crosslinks DNA, thereby inhibiting DNA and RNA synthesis. Also carbamoylates DNA and proteins, resulting in inhibition of DNA and RNA synthesis and disruption of RNA processing. Lomustine is lipophilic and crosses the blood-brain barrier
Hodgkins and non-Hodgkins lymphoma, malignant melanoma and epidermoid carcinoma of lung
Orally effective Nausea and vomiting, Nephrotoxicity, nerve dysfunction
C. Streptozotocin DNA damage pancreatic cancer Given I.V. Nausea and vomiting, nephrotoxicity, liver toxicity
A. Alkylating agents
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d. Ethylenimines 1. Mechanism of Action
2. Clinical application 3. Route 4. Side effects
A. Triethylene thiophosphoramide (Thio-TEPA)
DNA damage, CytochromeP450
Bladder cancer Given I.V. Nausea and vomiting, fatigue
B. Hexamethylmelamine(HMM)
DNA damage Advanced ovarian tumor Given orally after food
Nausea and vomiting, low blood counts, diarrhea
d. Triazenes 1. Mechanism of Action
2. Clinical application 3. Route 4. Side effects
A. Dacarbazine (DTIC) Blocks, DNA, RNA and protein synthesis
Malignant Melanoma, Hodgkins and non-Hodgkins lymphoma
Given I.V. Bone marrow depression, hepatotoxicity, neurotoxicity, bleeding, bruising, blood clots, sore mouths.
A. Alkylating agents
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Summary
Cancer ChemotherapyChapter 55. B.G. Katzung
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Tubulin Binding Agents
Polymerization
tubulin
Depolymerization
e.g., Vincristine, Vinblastine, VindesineVinorelbine: Inhibition of mitotic spindle formation by binding to tubulin.M-phase of the cell cycle.
e.g., Paclitexal: binds to tubulin, promotes microtubule formationand retards disassembly; results in mitotic arrest.Paclitexal (taxol)
Vincristine
B. Natural Products
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1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
A. Vincristine Cytotoxic: Inhibition of mitotic spindle formation by binding to tubulin.M-phase of the cell cycle.
Metastatic testicular cancer, Hodgkins and non-Hodgkins lymphoma, Kaposi’s sarcoma, breast carcinoma, chriocarcinoma, neuroblastoma
I.V. Bone marrow depression, epithelial ulceration, GI disturbances, neurotoxicity
B. Vinblastine Methylates DNA and inhibits DNA synthesis and function
Hodgkins and non-Hodgkins lymphoma, brain tumors, breast carcinoma, chriocarcinoma, neuroblastoma
I.V. Nausea and vomiting, neurotoxicity, thrombocytosis, hyperuricemia.
1. Antimitotic Drugs
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
Paclitaxel (Taxol) Cytotoxic: binds to tubulin, promotes microtubule formation and retards disassembly; mitotic arrest results
Melanoma and carcinoma of ovary and breast
I.V. Myelodepression and neuropathy
2. Antimitotic Drugs
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1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
A. Etoposide Binds to and inhibits Topoisomerase II and its function. Fragmentation of DNA leading to cell death, apoptosis.
Testicular cancer, small-cell lung carcinoma, Hodgkin lymphoma, carcinoma of breast, Kaposi’s sarcoma associated with AIDS
I.V. Myelosuppression, alopecia
B. Teniposide Same as above Refractory acute lymphocytic leukemia
I.V. Myelosuppression,
3. Epipodophyllotoxins (These are CCS)
Accumulation of single- or double-strand DNA breaks, the inhibition of DNA replication and transcription, and apoptotic cell death.
Etoposide acts primarily in the G2 and S phases of the cell cycle
Act on Topoisomerase II
35Cancer ChemotherapyChapter 55. B.G. Katzung
4. Antibiotics (CCS)
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
a. Dactinomycin (ACTINOMYCIN D)
It binds to DNA and inhibits RNA synthesis, impaired mRNA production, and protein synthesis
Rhabdomyosarcoma and Wilm's tumor in children;choriocarcinoma (used with methotrexate
I.V. Bone marrow depression, nausea and vomiting, alopecia,GI disturbances, and ulcerations of oral mucosa
b. Daunorubicin(CERUBIDIN)
Doxorubicin (ADRIAMYCIN)
inhibit DNA and RNA synthesis
Acute lymphocytic/granulocytic leukemias; treatment ofchoice in nonlymphoblastic leukemia in adults whengiven with cytarabine
I.V. Side effects: bone marrow depression, GI disturbances and cardiac toxicity (can be prevented by dexrazoxane)
inhibit DNA and RNA synthesis
Acute leukemia, Hodgkin's disease, non Hodgkin'slymphomas (BACOP regimen), CA of breast & ovary,small cell CA of lung, sarcomas, best available agentfor metastatic thyroid CA
I.V. Cardiac toxicity, Doxorubicin mainly affects the heart muscles, leading to tiredness or breathing trouble when climbing stairs or walking, swelling of the feet .
c. Bleomycin (BLENOXANE)
fragment DNA chains and inhibit repair
Germ cell tumors of testes and ovary, e.g., testicularcarcinoma (can be curative when used with vinblastine & cisplatin), squamous cell carcinoma
Given I.V. or I.M.
Mucosocutaneous reactions and pulmonary fibrosis; bonemarrow depression much less than other antineoplastics
Inhibit DNA and RNA syntheses
36Cancer ChemotherapyChapter 55. B.G. Katzung
5. Enzymes: L-asparaginase
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
L-asparaginase Hydrolyzes L-asparagine (to L-aspartic acid) an essential amino acid to many leukemic cells
Acute lymphocytic leukemia, induction of remission in acute lymphoblastic leukemia whencombined with vincristine, prednisone, and anthracyclines
I.V. or I.M.
Nausea and vomiting, Poor appetite, Stomach cramping, Mouth sores, Pancreatitis. Less common: blood clotting
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C. Antimetabolites
ReducedFolate Carrierprotein
MTXKills cells duringS-phase
(Folic acid analog)
MTX polyglutamatesAre selectively retainedIn tumor cells.
Folic acid is a growth factor that provides single carbons to the precursors used to form the nucleotides used in the synthesis of DNA and RNA. To function as a cofactor folate must be reduced by DHFR to THF.
* *
* * *
Cancer ChemotherapyChapter 55. B.G. Katzung
38Cancer ChemotherapyChapter 55. B.G. Katzung
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
1. Methotrexate
inhibits formation of FH4 (tetrahydrofolate) from folicacid by inhibiting the enzyme dihydrofolate reductase (DHFR); since FH4 transfersmethyl groups essential to DNA synthesis and hence DNA synthesis blocked.
Choriocarcinoma, acute lymphoblastic leukemia (children), osteogenic sarcoma, Burkitt's and other non-Hodgkin‘s lymphomas, cancer of breast, ovary, bladder, head & neck
Orally effective as well as given I.V.
bone marrow depression, intestinal lesions and interference with embryogenesis.Drug interaction: aspirin and sulfonamides displace methotrexatefrom plasma proteins.
C. Antimetabolites
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1. Mechanism of Action
2. Clinical application 3. Route 4. Side effects
2 Pyrimidine Analogs: Cytosine Arabinoside
inhibits DNA synthesis
most effective agent for induction of remission in acute myelocyticleukemia; also used for induction of remission acute lymphoblastic leukemia,non-Hodgkin's lymphomas; usually used in combination chemotherapy
Orally effective
bone marrow depression
1. Mechanism of Action
2. Clinical application 3. Route 4. Side effects
2 Purine analogs: 6-Mercaptopurine (6-MP) and Thioguanine
Blocks DNA synthesis by inhibiting conversion ofIMP to AMPS and to XMP as well as blocking conversion of AMP toADP; also blocks first step in purine synthesis.Feedback inhibitionblocks DNA synthesis by inhibiting conversion of IMP toXMP as well as GMP to GDP; also blocks first step in purine synthesis byfeedback inhibition
most effective agent for induction of remission in acute myelocyticleukemia; also used for induction of remission acute lymphoblastic leukemia,non-Hodgkin's lymphomas; usually used in combination chemotherapy
Orally effective
bone marrow depression,
40Cancer ChemotherapyChapter 55. B.G. Katzung
6. Drug ResistanceOne of the fundamental issue in cancer chemotherapy is the development of cellular drug resistance. It means, tumor cells are no longer respond to chemotherapeutic agents. For example, melanoma, renal cell cancer, brain cancer often become resistant to chemo.
A few known reasons:1.Mutation in p53 tumor suppressor gene occurs in 50% of all tumors. This leads to resistance to radiation therapy and wide range of chemotherapy.
2.Defects or loss in mismatch repair (MMR) enzyme family. E.g., colon cancer no longer respond to fluoropyrimidines, the thiopurines, and cisplatins.
3.Increased expression of multidrug resistance MDR1 gene which encodes P-glycoprotein resulting in enhanced drug efflux and reduced intracellular accumulation. Drugs such as athracyclines, vinca alkaloids, taxanes, campothecins, even antibody such as imatinib.
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Summary1. The main goal of anti-neoplastic drug is to eliminate the cancer cells
without affecting normal tissues.
2. Log-Kill Hypothesis states that a given therapy kills a percentage of cells, rather then a constant number, therefore, it follows first order kinetics. Aim for a favorable therapeutic index.
3. Early diagnosis is the key.
4. Combination therapy and adjuvant chemotherapy are effective for small tumor burden.
5. Two major classes of antineoplastic agents are:a. Cell Cycle Specific and b. Cell Cycle Non-Specific agents
5. Because chemotherapeutic agents target not only tumor cells, but also affect normal dividing cells including bone marrow, hematopoietic, and GI epithelium. Know what the side effects are.
6. Drug resistance is often associated with loss of p53 function, DNA mismatch repair system, and increased MDR1 gene expression.