Pharmacology of Antineoplastic Agents
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Pharmacology of Antineoplastic Agents. Outline of Lecture Topics:. Background Antineoplastic Agents: classification a. Cell Cycle Specific (CCS) agents b. Cell Cycle Non-Specific (CCNS) agents c. Miscellaneous (e.g., antibodies) agents Mechanisms of action Side Effects

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Pharmacology of antineoplastic agents

Pharmacology of Antineoplastic Agents

Outline of Lecture Topics:

  • Background

  • Antineoplastic Agents: classification

  • a. Cell Cycle Specific (CCS) agents

  • b. Cell Cycle Non-Specific (CCNS) agents

  • c. Miscellaneous (e.g., antibodies) agents

  • Mechanisms of action

  • Side Effects

  • Drug Resistance

Kishore Wary, Ph.D.

Dept Pharmacology

[email protected]


Pharmacology of antineoplastic agents

PART I

  • Background

  • Antineoplastic Agents

  • a. Cell Cycle Specific (CCS) agents

  • b. Cell Cycle Non-Specific (CCNS) agents

  • c. Miscellaneous (e.g., antibodies) agents


Pharmacology of antineoplastic agents

Cancer

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:

Carcinoma - skin or in tissues that line or cover internal organs. E.g., Epithelial cells. 80-90% reported cancer cases are carcinomas.

Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.

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.

Lymphoma - cells of the immune system that affects lymphatic system.

Myeloma - B-cells that produce antibodies- spreads through lymphatic system.

Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord.

(*National Cancer Institute, NCI)


Pharmacology of antineoplastic agents

Cancer Therapeutic Modalities (classical)

Surgery

Radiation

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 Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

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.

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

Cancer Chemotherapy (Background)

  • Most of the recent progress using antineoplastic therapy is based on:

    • Development of new combination therapy of using existing drugs.

    • Better understanding of the mechanisms of antitumor activity.

    • Development of chemotherpeutic approaches to destroying micrometastases

    • Understanding the molecular mechanisms concerning the initiation of tumor growth and metastasis.

    • Recognition of the heterogeneity of tumors

  • B. Recently developed principles which have helped guide the treatment of neoplastic disease

    • 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.


Pharmacology of antineoplastic agents

Cancer Chemotherapy

  • C. Malignancies which respond favorably to chemotherapy:

    • choriocarcinoma,

    • Acute leukemia,

    • Hodgkin's disease,

    • Burkitt's lymphoma,

    • Wilms' tumor,

    • Testicular carcinoma,

    • Ewing's sarcoma,

    • Retinoblastoma in children,

    • Diffuse histiocytic lymphoma and

    • Rhabdomyosarcoma.

D. Antineoplastic drugs are most effective against rapidly dividing tumor cells.


Pharmacology of antineoplastic agents

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 favorabletherapeutic index (aka therapeutic ratio).

LD50

-----

ED50

Therapeutic Index =

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 Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

F. The effects of tumor burden, scheduling, dosing, and initiation/duration of treatment on patient survival.

Untreated patients

Infrequent scheduling of

treatment courses.

Prolongs survival but does not cure.

More intensive and

frequent treatment.

Kill rate > growth rate.

Early surgical removal of the primary tumor decreases the tumor burden. Chemotherapy will remove persistant secondary tumors.

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

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 cardiotoxicity

      amifostine: reduces hematotoxicity, ototoxicity and neurotoxicity of alkylating agents


Pharmacology of antineoplastic agents

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.


Pharmacology of antineoplastic agents

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

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

Antineoplastic Agents


Pharmacology of antineoplastic agents

Chemotherapy: classification basedon 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 inhibitorsof 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.


Pharmacology of antineoplastic agents

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

Cell cycle specificity of Anti-Neoplastic Agents

Vincristine,

Vinblastine

Paclitaxel, Docetaxel

Cyclophosphamide

Bleomycin

Actinomycin D

M

G

0

resting

G

Hydrocortisone

G

2

1

G0 = resting phase

G1 = pre-replicative phase

G2 = post-replicative phase

S = DNA synthesis

M = mitosis or cell division

S

Actinomycin D

Purine antagonists

5-Fluorouracil

Methotrexate

Cytosine arabinoside

Cyclophosphamide

Methotrexate

5-Fluorouracil

6-Mercaptopurine

Cytosine arabinoside

6-Thioguanine

Daunomycin


Pharmacology of antineoplastic agents

Pharmacology of Antineoplastic Agents

PART II

  • Mechanisms of action

  • Side Effects

  • Drug Resistance

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

Topoisomerase Inh.

Alkylating agents

Antimetabolites

Asparaginase

Tubulin binders

Chemotherapy: Mechanisms of Action

1

DNA

Purines and

Pyrimidines

RNA

Protein

tubulin

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

Major Clinically Useful Alkylating Agents

Cancer Chemotherapy

Chapter 55. B.G. Katzung

Bis(mechloroethyl)amines

Nitrosoureas

Aziridines


Pharmacology of antineoplastic agents

An Example of DNA Crosslinking

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.


Pharmacology of antineoplastic agents

Alkylating Agents (Covalent DNA binding drugs)

The first class of chemotherapy agents used.

They stop tumour growth by cross-linking guaninenucleobases in DNA double-helix strands - directly attacking DNA.

This makes the strands unable to uncoil and separate.

As this is necessary in DNA replication, the cells can no longer divide.

Cell-cycle nonspecific effect

Alkylating agents are also mutagenic and carcinogenic

T

A

G

C

C

G

G

A

T

C

G

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

E.g., Mechlorethamine (Nitrogen Mustards)

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

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


Pharmacology of antineoplastic agents

Cyclophosphamide Metabolism

Inactive


Pharmacology of antineoplastic agents

Cyclophosphamide

Clinical Applications:

  • Breast Cancer

  • Ovarian Cancer

  • Non-Hodgkin’s Lymphoma

  • Chronic Lymphocytic Leukemia (CLL)

  • Soft tissue sarcoma

  • Neuroblastoma

  • Wilms’ tumor

  • Rhabdomyosarcoma

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

Cyclophosphamide

Major Side effects

Nausea and vomiting

Decrease in PBL count

Depression of blood cell counts

Bleeding

Alopecia (hair loss)

Skin pigmentation

Pulmonary fibrosis

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

Ifosphamide

  • Mechanisms of Action

  • Similar to cyclophosphamide

  • Application

  • Germ cell cancer,

  • Cervical carcinoma,

  • Lung cancer

  • Hodgkins and non-Hodgkins lymphoma

  • Sarcomas

  • Major Side Effects

  • Similar to cyclophosphamide


Pharmacology of antineoplastic agents

A. Alkylating agents

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

A. Alkylating agents


Pharmacology of antineoplastic agents

A. Alkylating agents

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

Summary

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

Tubulin Binding Agents

e.g., Vincristine, Vinblastine, VindesineVinorelbine: Inhibition of mitotic spindle formation by binding to tubulin.

M-phase of the cell cycle.

Polymerization

Vincristine

tubulin

a

e.g., Paclitexal: binds to tubulin, promotes microtubule formation

and retards disassembly; results in mitotic arrest.

Depolymerization

Paclitexal (taxol)


Pharmacology of antineoplastic agents

B. Natural Products

1. Antimitotic Drugs

2. Antimitotic Drugs


Pharmacology of antineoplastic agents

3. Epipodophyllotoxins (These are CCS)

Act on Topoisomerase II

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


Pharmacology of antineoplastic agents

4. Antibiotics (CCS)

Inhibit DNA and RNA syntheses

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

5. Enzymes: L-asparaginase

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

MTX polyglutamates

Are selectively retained

In tumor cells.

C. Antimetabolites

(Folic acid analog)

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.

Reduced

Folate

Carrier

protein

*

*

*

*

*

MTX

Kills cells during

S-phase

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

C. Antimetabolites

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

6. Drug Resistance

  • One 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:

  • Mutation in p53 tumor suppressor gene occurs in 50% of all tumors. This leads to resistance to radiation therapy and wide range of chemotherapy.

  • Defects or loss in mismatch repair (MMR) enzyme family. E.g., colon cancer no longer respond to fluoropyrimidines, the thiopurines, and cisplatins.

  • 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.

Cancer Chemotherapy

Chapter 55. B.G. Katzung


Pharmacology of antineoplastic agents

Summary

  • The main goal of anti-neoplastic drug is to eliminate the cancer cells without affecting normal tissues.

  • 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.

  • Early diagnosis is the key.

  • Combination therapy and adjuvant chemotherapy are effective for small tumor burden.

  • Two major classes of antineoplastic agents are:

  • a. Cell Cycle Specific and

  • b. Cell Cycle Non-Specific agents

  • 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.

  • Drug resistance is often associated with loss of p53 function, DNA mismatch repair system, and increased MDR1 gene expression.


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