Antitumor Drugs

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ANTITUMOUR DRUGS

Cancer - TERMINOLOGY

cancer = malignant neoplasm =malignant tumor (synonymous)

Neoplasm = new growth = tumour

Oncogenesis - the development of cancer

Oncogenes = cancer genes

- genes causing cancer

- agents causing Oncogens = carcinogens oncogenesis/carcinogen esis - agent causing mutation


Mutagen

- Spreading of a cancerous Metastasis growth by shedding cells that grow in other locations.

Neoplasia - Greek- new growth


- the process or formation of a neoplasm

Neoplasm

- an abnormal mass of tissue as a result of neoplasia.

In modern medicine, the term tumor is synonymous with a neoplasm that has formed a lump. Some neoplasms do not cause a lump.

Chemotherapy- the treatment of a disease by chemicals Cancer chemotherapy - the use of antineoplastic drugs or combination of these drugs to treat cancer

Cells the body's basic unit of life

The body is made up of many types of cells.


Normal, healthy cells grow and divide in a controlled way die to produce more cells to keep the body healthy. replaced with new cells
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Old or damaged cells

The cell cycle


= Sequence of events that take place within a cell cell replicates all its components bisect itself into 2 identical daughter cells

The cytoplasmic division of a cell at the end of mitosis or meiosis, bringing about the separation into two daughter cells

The phases of the cell cycle are:


G1- preparation of DNA synthesis S DNA synthesis G2 preparation for division M division into 2 daughter cells G0 resting state
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Cell Cycle Phases in Cell Division

G0

Origins of Cancer
genetic material (DNA) of a cell become damaged or changed producing mutations affect normal cell growth and division cells do not die when they should new cells form when the body does not need them

extra cells

mass of tissue;

Cancer cells have four characteristics that distinguish them from normal cells
Divide without control / uncontrolled proliferation

Loss of function because lack of capacity to differentiate

Able to invade adjacent tissues Can spread to other parts of the body through the blood and lymph systems (metastasis)
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Characteristics of cancer cells:

Failure in control of gene expression Heritable from cell to cell (mitosis)

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Cell division

Cell differentiation

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Cell Invasion

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Cancer Metastasis

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CANCER

There are more than 100 different types of cancer.

Most cancers are named for the organ or type of cell in which they start
eg, cancer that begins in the colon is called colon cancer; basal cells of the skin basal cell carcinoma.
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Not all tumors are cancerous

tumors can be benign or malignant.

Benign tumors aren't cancerous.

can often be removed, and in most cases, they do not recur Cells in benign tumors do not spread to other parts of the body.

Malignant tumors are cancerous.

Cells in these tumors can invade nearby tissues and spread to other parts of the body. The spread of cancer from one part of the body to another is called metastasis.
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Carcinogenesis

is the process by which normal cells are transformed into cancer cells; generation of benign and malignant tumors caused by mutation of the genetic material (proto-oncogenes or tumor supressor genes) of normal cells, which disturbs the normal balance between proliferation and cell death*

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Theories of carcinogenesis
1. Heredity (proto-oncogenes: & tumor suppressor genes) 2. Viral oncogenes 3. Chemicals & radiations 4. Failure of immune surveillance

HEREDITY

Cancer a disease of abnormal gene function. Genes pieces of DNA that contain the instructions on:
how to make the proteins that the body needs to function when to destroy damaged cells how to keep the cells in balance

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2 common genes in cancer:


Oncogenes (eg. Ras, C-myc) can cause cancer mutated forms of proto-oncogenes proto-oncogenes mutation activates oncogene cell grow out of control cancer Tumor suppressor genes (Rb, p53) stop cancer from developing Normal genes that slow down cell division, repair DNA mistakes/damages and tell cells when to die (via apoptosis)

A mutation= Abnormal change in a gene

2 types of gene mutations:


Inherited passed via the ovum/sperm; in every cell in the body Acquired somatic mutations, occurs in one cell and then is passed on to any new cells that are the offspring of that cell
Cause most cases of cancer Caused by things that we are exposed to eg cigarette smoke, radiation, hormones, diet

ABBREVIATIONS FOR GENES

Oncogenes are described by a two or threeletter code Usually derived from their first discovery
Ras oncogene a gene originally identified in rat sarcomas Abl first discovered in Ableson virus

Sometimes, the three-letter code is followed by a letter or number Allocation of a number indicates that the genes

Types of Cancer
Carcinoma (epithelial, or surface, tissue of organs) Sarcoma (bone, cartilage, connective tissue, fatty tissue) Myeloma (bone marrow plasma cells) Lymphoma (lymph system: lymphocytes & nodes) Leukemia (blood forming tissue)-flood of immature WBCs

3 main approaches to treat established cancer:


1) Surgical excision 2) Irradiation (x-rays, gamma rays) 3) Chemotherapy

Chemotherapy may be used on its own or as an adjunct to other forms of therapy.


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Treatment strategies for cancer patients

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 (to relieve or lessen without curing)

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Treatment strategies:

The ultimate goal of treatment to achieve a cure (long term, diseasefree survival) A true cure requires elinimation of EVERY neoplastic cell

If cure is becomes (cancer) enlarging

not achievable the goal control of the disease to stop the cancer from and spreading to extend

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Treatment strategies:

Initial/early stage neoplastic cell burden can be reduced by surgery and/or by radiation, followed by chemotherapy, immunotherapy or combination of these treatment

In advanced stages of cancer possibility of controlling the cancer is far from reality
Thus, the goal of treatment is palliation (alleviation /lessening of symptoms and avoidance of life-threatening toxicity due to cancer)

Chemotherapeutic drugs may be used to;

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Treatment strategies: Indications for treatment

Chemotherapy (Ctx) is indicated when neoplasms are disseminated/spread and are not responsive to surgery Ctx is also used as supplemental treatment i.e. to attack micrometastases following surgery & radiation treatment Adjuvant ctx Neoadjuvant ctx Ctx given prior to the surgical procedures in an attempt to shrink the cancer
A lessening of intensity or degree

Maintenance ctx Ctx given in lower doses


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Treatment strategies: Indications for treatment (cont)

American Cancer Society cancer remission is a "period of time when the cancer is responding to treatment or is under control. In a complete cancer remission, all the signs and symptoms of the disease disappear continue for several years considered cured Remission successsfully treated + safe

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Treatment strategies: Tumor susceptibility and the growth cycle of tumor cells

Susceptible affected

easily

influenced

or

The fraction of tumor cells that are in the replicative cycle influences their susceptibility to cancer
Rapidly dividing cells more sensitive to drugs
eg. Cells of buccal mucosa, bone marrow, GI mucosa & hair

Slowly proliferating less sensitive

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Principles of cancer chemotherapy

To cause a lethal cytotoxic event or apoptosis in the cancer cell arrest a tumors progression

The attack is generally directed toward DNA or against metabolic sites essential for cell replication

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Eg

Methotrexate inhibit dihydrofolate reductase inhibition of purine (adenine / guanine) ring biosynthesis Cytarabine terminates DNA chain elongation and/or incorporated
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Both normal & tumor cells go through growth/cell cycles

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Cell-cycle specificity of drugs (cont)

Cell-cycle spesific (CCS) drugs = chemotherapeutic agents that are effective only against cycling /rapidly replicating cells
Egs. Antimetabolites, peptides antibiotics bleomycin

Cell-cycle nonspecific (CCNS) drugs = effective for both slowly proliferating cells (in solid tumors)
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Tumor growth rate

The growth rate of most solid tumors in vivo is initially rapid. But as the tumor size increases, the growth rate usually decreases.
Due to unavailability of nutrients and O2 caused by inadequate vascularization and lack of blood circulation

Reducing the tumor burden thru surgery or radiation often promotes the recruitment of the remaining cells into active

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The log kill hypothesis:


Destruction of cancer cells by cytotoxic agents follows first-order kinetics: a given dose killing a constant proportion of a cell population rather than a constant number of cells

eg. A 3-log kill dose of an effective drug will reduce a cancer cell population of 1012 cells to 109. In this case, the dose reduces the numbers of cells by three orders of magnitude, or 3 logs
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Combinations of drugs

Combination-drug chemotherapy is more successful than single drug treatment in most of the cancers for which chemotherapy is effective

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Combinations of drugs (cont)

Cytotoxic agents with qualitatively different toxicities, and with different molecular sites and mechanism of action are usually combined at full doses results in higher response rates due to additive cytotoxic effects and nonoverlapping host toxicities In contrast, agents with similar dose-limiting toxicities (myelosuppression, nephrotoxicity

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Advantages of drug combinations:


1) Provide maximal cell killing within the range of tolerated toxicity 2) Effective against a broader range of cell lines in the heterogenous tumor populations 3) May delay or prevent the development of resistant cell lines

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Combination chemotherapy

Many cancer treatment protocols have been developed and each one is applicable to a particular neoplastic state

They are usually identified by an acronym /short form Eg. POMP a common regimen used for the tx of acute lymphocytic leukemia; consist of Prednisolone, Oncovin
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Eg. of drug combinations:


Diagnosis Current drug therapy of choice Acute lymphocytic Induction: vincristine + prednisone; leukemia Maintenance: mercaptopurine, methotrexate and cyclophosphamide in various combinations Breast carcinoma (early stage)

Cyclosphosphamide + methotrexate & fluorouracil

Ewings sarcoma
Cyclosphosphamide + doxorubicin & vincristine

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Problems associated with chemotherapy:


1) Resistance 2) Toxicity 3) Treatment-induced tumors

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1) Resistance

Cancer drugs are toxins that produce a lethal threat to the cells therefore the cells have evolved complex defense mechanisms to protect themselves from chemical toxins, including chemotherapeutic agents Drug resistance is a major problem in cancer chemotherapy. In many cases, the resistance mechanisms involve changes in gene expression in neoplastic cells that can

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Problems associated with chemotherapy : Resistance

Some neoplastic cells (eg. Melanoma) are naturally resistant to most anticancer drugs

Other tumor types may acquire resistance by mutating, particularly after prolonged administration of suboptimal drug doses
The development of drug resistance
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Problems associated with chemotherapy : Toxicity


2) Toxicity Therapy aimed at killing rapidly dividing cancer cells also affects normal cells undergoing rapid proliferation (eg. Cells of buccal mucosa, bone marrow, GI mucosa & hair), contributing to the toxic symptoms of chemotherapy
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Adverse effects of chemotherapeutic agents


Most antineoplastic agents have a narrow therapeutic index (TI) TI = The ratio between the toxic dose and the therapeutic dose of a drug

Severe vomitting, stomatitis, bone marrow suppression, and alopecia occur to a lesser or greater extend during therapy with all antineoplastic agents

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Adverse effects of chemotherapeutic agents (cont)

Common adverse effect eg. Myelosuppression

Adverse reactions confined to specific agents: Cardiotoxicity doxorubicin pulmonary fibrosis bleomycin

The duration of the side effects varies widely..


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Side effects of cancer chemotherapy drug 2 distinct categories:

Immediate effects
Occur soon after cancer chemotherapy drug administration Eg. Nausea, vomiting, mouth ulcers, blistering and necrosis of skin

Delayed effects
Observed sometime after drug therapy starts Eg. Suppression of bone marrow cells, myelosuppression (decreased production of blood cells), alopecia

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Minimizing adverse effects

Some toxic reactions may be eased by:


Cytoprotectant drugs
Perfusing the tumor locally (forcing the drugs through blood vessel/lymphatics)

Promoting intensive diuresis (increased urine production) to prevent bladder toxicities


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Problems associated with chemotherapy : treatmentinduced tumors

Because most antineoplastic agents are mutagens, neoplasms may arise 10 or more years after the original cancer was cured.
(mutagens = agent that changes the genetic material, usually DNA)

Treatment-induced neoplasms are especially a problem after therapy with alkylating agents (???)

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ANTICANCER DRUGS

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ANTICANCE R DRUGS
ANTIMETABOLITES MICROTUBULE INHIBITORS

ALKYLATING AGENTS
MONOCLONAL ANTIBODIES

ANTITUMOR ANTIBIOTICS

OTHERS STEROID HORMONES & THEIR ANTAGONISTS

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(1) ANTIMETABOLITES

Antimetabolites are structurally related to normal compounds that exist within the cell They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis Their maximal cytotoxic effects are in Sphase therefore they are cell-cycle

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Antimetabolites:

Methotrexate , 6-mercaptopurine, 6thioguanine fludarabine, cladribine, 5-fluorouracil, capecitabine floxuridine, cytarabine, gemcitabine

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ANTIMETABOLITES: mechanism of actions


METHOTREXATE, MTX MTX is structurally related to folic acid and acts as an antagonist of folic acid/folate by inhibiting dihydrofolate reductase (DHFR) - the enzyme that converts folic acid to its active form, tetrahydrofolic acid AND also required by thymidylate synthetase to provide methyl donors for the formation of thymidylate, essential for DNA synthesis. Tumor cell resistance mechanisms include: decreased drug accumulation and changes in the drug sensitivity or activity of DHFR 6MERCAPTOPURI NE (6MP) & 6THIOGUANINE (6TG) =purine antimetabolites 6MP and 6TG are activated by hypoxanthine-guanine phospho ribosyl transferases (HGPRTase) to toxic nucleotide forms that inhibit several enzymes involved in purine metabolism. Resistance tumor cells have decreased activity of HGPRTase or they may increase their production of alkaline phosphatases that inactivate the toxic nucleotides

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ANTIMETABOLITES: mechanisms of actions


FLUOROURACI L& CYTARABINE = pyrimidine antimetabolites Fluorouracil is biotransformed to 5-fluoro-2-deoxyuridine5-monophosphate (5-FdUMP), which inhibits thymidylate synthase and leads to thymineless death of cells

Cytarabine (cytosine arabinoside- AraC) is activated by kinases to AraCTP, an inhibitor of DNA polymerases
*of all the antimetabolites, cytarabine is the most specific for the S-phase of the tumor cell cycle Resistance to cytarabine can occur through decreased uptake of AraC or a decreased conversion to AraCTP

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Purine antimetabolites (and fluorouracil) are effective after oral administration The pyrimidine antimetabolites are usually given intravenously

Antimetabolites: pharmacokinetics

Antimetabolites: clinical uses


Antimetabolites are used in drug combinations for acute leukemias Cytarabine is an important component for the treatment of acute myelogenous leukemia (AML) MTX, alone or combined with other drugs, is effective in choriocarcinoma, non-Hodgkins and cutaneous T cell lymphomas Fluorouracil is only useful in the tx of solid tumors and 63 as topical agent for skin cancers

Antimetabolites: toxicity

Common adverse effects include bone marrow suppression and toxic effects on the skin and GI mucosa (mucositis). Purine antimetabolites may cause dosedependent hepatic dysfucntion The toxic effects of methotrexate on normal cells may be reduced by administration of folinic acid (leucovorin) this strategy is called leucovorin rescue
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(2) ANTITUMOR ANTIBIOTICS


The antitumor antibiotics owe their cytotoxic action primarily to: 1) their interactions with DNA (through intercalation*), leading to disruption of DNA function

*intercalation = Insertion of a flat aromatic molecule between adjacent base pairs of the DNA double helix.

2)
3)

Their abilities to topoisomerases (I and II) Produce free radicals

inhibit

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ANTITUMOR ANTIBIOTICS
Dactinomycin Doxorubicin & daunorubicin Bleomycin

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ANTITUMOR ANTIBIOTICS: MECHANISM OF ACTIONS Dactinomycin this is a CCNS drug that binds to double-stranded DNA and inhibits DNA-dependent RNA synthesis

Anthracyclins: This is a CCNS drugs - can intercalate between base Doxorubicin & pairs to block DNA and RNA synthesis, cause membrane daunorubicin disruption and generation of free radicals that lead to cardiotoxicity

Bleomycin

This agent is a mixture of glycopeptides that generate free radicals which bind to DNA and cause DNA strand breaks and inhibit DNA synthesis. These peptides are CCS drugs active in the G2 phase of the tumor cell cycle

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Important features include: 1) the metabolism of anthracyclins by liver enzymes to form both active and inactive metabolites that are excreted in the bile
2)

Antitumor antibiotics: pharmacokinetics

the inactivation of bleomycins by tissue aminopeptidases- but some renal clearance of intact drug also occurs
The short half-life of dactinomycin, with intact drug excreted in the bile
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3)

Antibiotics: clinical use

Doxorubicin is a component of the tx regimens used in Hodgkins disease, myelomas and sarcomas Bleomycin is a component of the tx regimen for testicular carcinoma Dactinomycin is used in melanomas and Wilms tumor

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Antitumor antibiotics: toxicity


Anthracyclins: -These drugs cause bone marrow suppression, GI distress and severe alopecia. Their most distinctive adverse effect is cardiotoxicity Bleomycin: -Pulmonary toxicity develops slowly and is dose-limiting. -Hypersensitivity reactions (chills, fever, anaphylaxis) and mucocutaneous reactions (alopecia, blisterformation, hyperpigmentation) are common Dactinomycin: -this drug causes bone marrow suppression, skin 70 reactions and GI irritation

(3) ALKYLATING AGENTS

Before their use in chemotherapy, alkylating agents were better known for their use as sulfur mustard, ("mustard gas") and related chemical weapons in World War I.

1943- Goodman & Gilman were prompted to study nitrogen mustards as a potential treatment for cancer following an incident in Bari, Italy, where survivors exposed to mustard gas became leukopenic*.

*a decrease in the number of white blood cells (leukocytes)


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ALKYLATING AGENTS (cont)

An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group (CnH2n+1) to DNA. The alkyl group is attached to the guanine base of DNA of cancer cells Exert their cytotoxic effects by forming reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N7 postion of guanine in DNA double-helix strands. This leads to cross-linking of bases, abnormal base-pairing, makes the strands unable to uncoil and separate and/or DNA strand breakage.. As this is necessary in DNA replication, the cells can no longer divide.

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ALKYLATING AGENTS (cont)

Alkylating agents do not discriminate between cycling and resting cells, but most toxic for rapidly dividing cells They are used in combination with other agents to treat a wide variety of lymphatic and solid cancers. In addition to being cytotoxic, all are mutagenic and carcinogenic and can lead to second malignancies, such as acute leukemia
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ALKYLATING AGENTS
Mechlorethamine Cyclophosphamide & ifosfamide Nitrosoureas Dacarbazine Temozolomide Others: melphalan, chlorambucil, busulfan

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ALKYLATING AGENTS (cont)

Tumor cell resistance to alkylating agents occurs through increased DNA repair, decreased drug permeability, or the production of trapping agents as thiols (eg. Glutathione).
Some tumor cells increase their production of thiol trapping agents, which interact with the reactive molecular species formed by the anticancer drugs inactive

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ALKYLATING AGENTS: clinical uses

These agents are important in combination regimens for the therapy of lymphomas, leukemias and myelomas.
Eg. Mechlorethamine is a component of a multidrug regimen for Hodgkins disease

Cyclosphosphamide is used in ovarian cancers and neuroblastoma


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ALKYLATING AGENTS: toxicity

Common toxic effects include: Bone marrow suppression leukopenia, thrombocytopenia GI irritation Changes in gonadal function The use of cyclosphosphamide is associated with a high incidence of alopecia & hemorrhagic cystitis Busulfan adrenal insufficiency, pulmonary fibrosis and increased skin

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(4) MICROTUBULE INHIBITORS

The mitotic spindle is part of a larger, intracellular skeleton (cytoskeleton) that is essential for the movements of structures occurring in the cytoplasm of all eukaryotic cells it consists of chromatin + microtubules (composed of protein tubulin)
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MICROTUBULE INHIBITORS

The mitotic spindle is essential for the equal partitioning of DNA into two daughter cells that are formed when a cell divides Several plant-derived substances used as anticancer drugs disrupt this process by affecting the equilibrium between the polymerized and depolymerized forms of the
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MICROTUBULE INHIBITORS

Vincristine and vinblastine


Referred to as vinca alkaloids Periwinkle/ Vinca rosea

Paclitaxel and docetaxel


Pacific yew tree /Taxus brevifolia

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VINCRISTINE (VX) & VINBLASTINE (VBL) Mechanism of action VX and VBL are both cell-cycle specific and phase specific, because they block mitosis in metaphase (M phase). Their binding to the microtubular protein, TUBULIN blocks the ability of tubulin to polymerize to form microtubules. Instead paracrystalline aggregates consisting of tubulin dimers and the the alkaloid drug are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cancer cell proliferation.

Resistance

Resistant tumor cells have been shown to have enhanced efflux of VX and VBL via p-glycoprotein in the cell membrane. Alterations in tubulin structure of the tumor cells may also affect binding of the vinca alkaloids

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VINCRISTINE (VX) & VINBLASTINE (VBL)

Pharmacokinetic IV injection of these agents leads to rapid cytotoxic effects and cell destruction. This is turn can cause hyperuricemia (high uric acid in blood) due to the oxidation of purines that are released from fragmenting DNA molecules. The hyperuricemia is ameliorated by administration of the xanthine oxidase-inhibitor Allopurinol.
The vinca alkaloids are concentrated and metabolized in the liver by the cytochrome P450 pathway. They are excreted into bile and feces. Doses must be modified in patients with impaired hepatic function or biliary obstruction

Adverse effects

Phlebitis, alopecia

cellulitis, nausea, vomiting, diarrhea and


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PACLITAXEL & DOCETAXEL Mechanism of action Both drugs are active in the G2/M phase of the cell cycle. They bind reversibly to the B-tubulin subunit, but unlike the vinca alkaloids, they promote polymerization and stabilization of the polymer. Thus, they shift the depolymerization polymerization process to accumulation of microtubules. The overly stable microtubules formed are nonfunctional, and thus, chromosome desegregation does not occur. This results in cell death.

Resistance

Like the vinca alkaloids, resistance has been associated with the presence of amplified Pglycoprotein or a mutation in the tubulin structure

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PACLITAXEL & DOCETAXEL Pharmacokinetic Both drugs have a large volume of distribution but neither enter the CNS. Hepatic metabolism by the cytochrome P450 system and biliary excretion are responsible for their elimination into the stool/feces.

Adverse effects

The dose-limiting toxicity of both drugs is neutropenia (low neutrophils). Patients with fewer than 15000 neutrophils/mm3 should not be given these agents. Treatment with granulocyte-colony-stimulating factor (Filgrastim) can help to reverse neutropenia.

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(5) STEROID HORMONES & THEIR ANTAGONISTS


Tumors that are steroid hormone-sensitive may be either: 1) hormone responsive in which the tumor regresses following tx with a specific hormone hormone tx is only palliative, except in the case of cytotoxic effect of glucocorticoids (eg. Prednisone) at higher doses on lymphomas (cancer in the lymphatic cells of the immune system)
2)

Hormone-dependent in which removal of a hormonal stimulus causes tumor regression removal of hormonal stimuli from hormonedependent tumors can be accomplished by surgery (orchiectomy for patients with advanced prostate cancer) or by drugs (eg. Antiestrogen tamoxifen)

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STEROID HORMONES & THEIR ANTAGONISTS

For a steroid hormone to influence a cell, that cell must have intracellular (cytosolic) receptors that are specific for that hormone

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STEROID HORMONES & THEIR ANTAGONISTS

Prednisone Tamoxifen Aromatase inhibitors Progestins Leuprolide & goserelin Estrogens Flutamide, nilutamide & bicalutamide

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PREDNISONE

Mechanis m of action

Prednisone is a potent, synthetic , antiinflammatory corticosteroid with less mineralocorticoid activity than cortisol.
Prednisone itself is inactive and reduced to prednisolone hydroxysteroid dehydrogenase. then binds to a receptor that production of specific proteins. must first be by 11-BThis steroid triggers the

Resistanc resistance is associated with an absence of e the receptor protein or a mutation that lowers receptor affinity for the hormone.
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PREDNISONE Pharmacokinetic Prednisone is readily absorbed orally. It is bound to plasma albumin and transcortin. It undergoes 11-Bhydroxylation to prednisolone in the liver. Prednisolone is the active drug and it is glucuronidated and excreted into the urine along with the parent compound.

Adverse effects

Include infection, due to its immunosuppressant action, ulcers and pancreatitis

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(6) MONOCLONAL ANTIBODIES

Monoclonal antibodies (Mab) have become an active area of drug development for anticancer therapy and other nonneoplastic diseases, because they are directed at specific targets and often have fewer adverse effects MAb are created from B lymphocytes (from immunized mice/hamsters) fused with immortal B lymphocytes tumor cells the resulting hybrid can be
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MONOCLONAL ANTIBODIES (cont)

Recombinant technology has led to the creation of humanized abs that overcome the immunologic problems following administration of mouse (murine) abs.

Several MAbs available in US: Trastuzumab, rituximab, bevacizumab and cetuximab

Others: (1) gemtuzumab ozogamicin a MAb conjugated with a plant toxin that binds to

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(7) OTHER CHEMOTHERAPEUTIC AGENTS Platinum coordination complexes Irinotecan & topotecan Etoposide Imatinib Gefitinib Procarbazine L-asparagine Interferons

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THE END

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