الرحمن الله بسمالرحيم

Chemotherapy In Haematological Diseases

ByShimaa Abdallah AhmedClinical haematology unit

2013

Introduction Cell cycle Definition of terms Commonly used cytotoxic drugs (actions ,uses , toxicity and resistance).1. Alkylating agents2. Antimetabolites3. Anti-Mitotic Agents4. Antibiotics 5. Enzymes

L-Asparaginase 6. Hydroxyurea

Outline

Chemotherapy  is the treatment of cancer with one or more cytotoxic anti-neoplastic drugs ("chemotherapeutic agents") as part of a standardized regimen.

Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.

Introduction

Certain chemotherapeutic agents also have a role in the treatment of other conditions, including ankylosing spondylitis, multiple sclerosis, Crohn's disease, psoriasis, psoriatic arthritis, systemic lupus erythematosus, rheumatoid arthritis, and scleroderma.

 conditioning regimens in SCT◦Cyclophosphamide ,busalfan ,melphlan

Introduction

• cancer is the uncontrolled growth of cells coupled with malignant behaviour: invasion and metastasis. It is caused by the interaction between genetic susceptibility and environmental factors.  these factors lead to accumulations of genetic mutations in oncogenes(genes that promote cancer) and tumor supressor genes (genes that help to prevent cancer), which gives cancer cells their malignant characteristics, such as uncontrolled growth.

Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiation therapy or surgery.

Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. This type of chemotherapy is used for curative intent.

Consolidation chemotherapy is the given after remission in order to prolong the overall disease free time and improve overall survival. The drug that is administered is the same as the drug that achieved remission.

Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used.

Definition of terms

Combination chemotherapy 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. Also, the drugs can often be used at lower doses, reducing toxicity.

Neoadjuvant chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor. It is also given to cancers with a high risk of micrometastatic disease.

Adjuvant chemotherapy is given after a local treatment (radiotherapy or surgery). It can be used when there is little evidence of cancer present, but there is risk of recurrence.

Maintenance chemotherapy is a repeated low-dose treatment to prolong remission.

Salvage chemotherapy is potentially curative high dose ,compination regimens,given in patient with failed or recurrent after many curative regimens .

palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy.

since these drugs act by inhibiting cell division, the most common side effects are those that occur in areas of the body where cell replication occurs, such as

A. the GI mucosa (nausea, vomiting, diarrhœa), B. the bone marrow (myelosuppression causing

leukopænia and other blood dyscrasias), andC. hair follicles (alopecia).D.   Most antineoplastics have less effects on those

cells that are non-dividing (kidney, heart) and effects on these organs are often the result of damage to portions of the cell other that DNA. 

Originally derived from mustard gas used in the war, They are so named because of their ability to alkylate many molecules, including proteins, RNA and DNA.

This causes "mistakes" in the DNA that may result in mispairing, substitutions, or excision. 

 This leads to a form of programmed cell death called apoptosis.

  Alkylating agents are non-cell-cycle specific the higher the dose, the more damage to DNA

Alkylating agents

The subtypes of alkylating agents are Nitrogen mustards include mechlorethamine, 

cyclophosphamide, melphalan and  chlorambucil. Alkylsulphonate Busulfan Nitrosoureas include  carmustine (BCNU), lomustine

 (CCNU) Tetrazines includes dacarbazine others include Cisplatin and derivatives include cisplatin,

carboplatin and oxaliplatin   Non-classical alkylating agents include procarbazine .

Two DNA bases that are cross-linked by a nitrogen mustard. Different nitrogen mustards will have different chemical groups (R). The nitrogen mustards most commonly alkylate the N7 nitrogen of guanine (as shown here) but other atoms can be alkylated

Nitrogen Mustards Meclorethamine◦ Uses -- (MOPP) for Hodgkin's disease and mycosis

fungoids. ◦ Toxicity -- lacrimation, local damage (irritation,

sloughing, necrosis) if extravasation occurs (sodium thiosulphate)

Cyclophosphamide◦ Uses -- Lymphoma, chronic leukæmia, numerous

carcinomas,, breast cancer, multiple myeloma, neuroblastoma and retinoblastoma in children.

◦ Toxicity -- pulmonary fibrosis,cardiotoxicity.  Other toxicities include a syndrome of inappropriate ADH (SIADH), ridging of nails,  and hæmorrhagic cystitis.  The hæmorrhagic cystitis may be diminished by the administration of 2-mercaptoethane sulphonate or MESNA, which donates sulphydryl groups to inactive the drug.

Ifosfamide◦Uses -- Germ cell testicular cancer,

sarcomas and salvage therapy in lymphoma( ICE )

◦ Toxicity -- is nephrotoxicity and neurotoxicity (coma, deathNephrotoxicity may be diminished by 2-MESNA.

Melphalan◦Uses -- Multiple myeloma, breast and ovarian

cancers  Chlorambucil ◦use-- Chronic lymphocytic leukemia, non-

Hodkin's lymphoma and macroglobulinæmia◦Toxicity -- Relatively side effect free, Pulmonary

toxicity is rare. Alkylsulphonate(Busulfan)◦Use -- Chronic granulocytic leukæmia◦Toxicity -- pulmonary fibrosis and Addison-like

syndrome .

Carmustine (BCNU) and Lomustine (CCNU)-- a chloronitrosourea◦ Uses -- Hodkin's and non-Hodkin lymphoma, brain

tumours, multiple myeloma (mini –BEAM), malignant melanoma,mycosis fungoides (LOCAL)

◦ Toxicity -- Pulmonary fibrosis, Liver and Renal Failure.  Triazene (Dacarbazine)◦ Uses -- Malignant melanoma, Hodkin's

lymphoma(ABVD), soft tissue cancers, and sarcomas Toxicity -- GI upset, mild to moderate BMS, flu-like syndrome

Nitrosoureas -- These agents are highly lipophilic

◦ Mechanism of Action -- These agents are bioactivated through substitution of chloride ions for hydroxyl groups.  The active moiety then interacts with DNA, forming both inter- and intra-strand links (especially to the DNA base guanine)

◦ Uses – salvage therapy for lymphoma(DHAP,ESHAP),Ovarian, testicular, bladder, head, neck, and endometrial cancers

◦ Toxicity -- Ototoxicity and Neurotoxicity nephrotoxicity (this may be attenuated by hydration and diuresis), and electrolyte disturbances (probably mediated by the liberated chloride ions).

Carboplatin◦ Uses –salvage therapy for lymphoma(ICE) The same as

cisplatin Toxicity -- Fewer toxicities that cisplatin.

Cisplatin

Mechanism of Action -- Procarbazine methylates DNA, essentially acting in a manner similar to the alkylating agents.  Additionally, free radical formation may contribute to the action of procarbazine.  Both of these actions will decrease DNA, RNA, and protein synthesis.

Use -- Hodkin's lymphoma(MOPP) Toxicity -- neurotoxicity (including

behavioural changes), and a disulfiram-like reaction.

Procarbazine

1. Folate Antagonists -- Methotrexate◦ Mechanism of Action -- Methotrexate inhibits dihydrofolate

reductase◦ Methotrexate is primarily active during the S phase of the

cell cycle◦ The toxic effects of methotrexate may be reversed by the

administration of leucovorin, which is a fully reduced folate co-factor.  Leucovorin "rescue“

◦ Uses -- Acute lymphocytic leukæmia,aggressive lymphoma (MACOP-B) choriocarcinoma, mycosis fungoides, osteogenic sarcoma, and breast.

◦ Toxicity -- pneumonitis.  Chronic side effects (seen with methotrexate as a immunosuppressant in rheumatoid arthritis or psoriasis) include hepatic fibrosis and cirrhosis.

Antimetabolites

5-Fluorouracil (5-FU) and Floxuridine -- these drugs are analogues of uridine◦ Mechanism of Action -- Both of these agents are

metabolised in vivo to F-UTP and F-dUTP which inhibit RNA and DNA synthesis respectively

◦ Uses --Breast, GI, ovarian, cervical, bladder, prostate, and pancreatic cancers and hepatoma.

Cytarabine (cytosine arabinoside) -- a cytosine analogue◦ Mechanism of Action -- activated to the nucleotide form to

substitute for CTP, inhibiting DNA chain elongation, as previously described. Uses -- Acute granulocytic and lymphocytic leukæmias.

◦ Toxicity -- DLT = Neurotoxicity (especially in older adults). 

2. Pyrimidine Antagonists

purine antagonists appear to substitute for guanine or adenosine to decrease/inhibit metabolic reactions that are necessary to form the guanine or adenine that will be incorporated into DNA.

  6-Mercaptopurine Uses -- Leukæmias◦ Toxicity -- jaundice (33%), and hyperuricæmia and

hyperuricosuria  Azathioprine -- this drug is a 6-MP derivative

that is used for its immunosuppressive effects.  The mechanism of action is the same as 6-MP.

3. Purine Antagonists

Fludaribine -- an adenine analogue◦ Mechanism of Action -- Fludaribine inhibits DNA polymerase.◦ Uses -- Chronic lymphocytic leukæmia ◦ Toxicity --chills, fever, neurotoxicity, and pulmonary toxicity.

Cladribine -- an adenine analogue◦ Uses -- Cladribine is the drug of choice of hairy cell leukæmia

Pentostatin◦ Mechanism of Action -- Pentostatin inhibits adenosine

deaminase to increase intracellular levels of adenosine and deoxyadenosine nucleotides. 

◦ Uses -- hairy cell leukæmia and chronic lymphocytic leukæmia

◦ Toxicity -- neurotoxicity, nephrotoxicity.  Also, , rash, and hepatotoxicity.

Mechanism of Action -- The vinca alkaloids block cellular mitosis by directly binding to and inhibiting tubulin formation, specifically during metaphase. 

Vinblastine◦ Uses -- metastatic testicular cancer and

lymphoma(ABVD).◦ Toxicity -- SIADH (rare), alopecia, and

sloughing/necrosis with extravasation. Vincristine◦ Uses -- Hodkin's and non-Hodkin lymphoma, pediatric

leukæmias, numerous solid tumours ◦ Toxicity -- Neurotoxicity

Natural Products Anti-Mitotic Agents

Paclitaxel (Taxol) and Docetaxel ◦ Uses -- Ovarian and breast cancers ◦ Toxicity -- These agents may also cause bradycardia

(early) and silent ventricular tachycardia (late).  Epipodophyllotoxins -- Mechanism of Action -- The epipodophyllotoxins form a

ternary complex with DNA and topoisomerase II, causing double-strand breakage. (Late S,G2 phase)

Etoposide◦ Uses -- Testicular, breast,  and small-cell lung cancers,

salvage therapy non-hodkin lymphoma (ICE,ESHAP,mini BEAM), leukæmia, and Kaposi's sarcoma.

Teniposide◦ Uses -- Primarily used for refractory acute lymphocytic

leukæmia in children 

Anthracycline Antibiotics Mechanism of Action –

DNA intercalation, preventing DNA and RNA synthesis, single and double

stranded breaks (via topoisomerase II).  form free radicals (ferrous ion and oxygen are

necessary catalysts for their formation) which may directly damage DNA, RNA, or cellular components, accounting at least in part for the cytotoxic effects of the drugs. 

◦ anthracycline antibiotics form free radicals that responsible for the cardiotoxicity associated with these drugs, through damage to the contractile structures of the myocardium.  by the administration of an anti-oxidant (alpha-tocopherol) or an iron chelating agent (dexrazoxane).

Antibiotics--

Daunorubicin (daunomycin, rubidomycin)◦ Uses -- Primarily used for leukæmias◦ Toxicity -- cardiotoxicity (manifest early as arrhythmia, late as

congestive failure. Doxorubicin (doxomycin) Uses -- Broader spectrum of activity, used in several

solid tumours Idarubicin Mitoxantrone -- these are derivatives of the

anthracycline antibiotics◦ Mechanism of Action -- The anti-neoplastic effects of

mitoxantrone are due to DNA intercalation.  It does not exhibit the degree of free radical formation and therefore essentially lacks the cardiotoxic effects of others in the class.

Anthracycline Antibiotics

Actinomycin D (Dactinomycin)◦ Mechanism of Action -- Dactinomycin intercalates with

DNA to prevent DNA transcription by RNA polymerase,Dactinomycin causes strand breaks by decreasing topoisomerase II activity.

◦ Uses -- Rhabdomyosarcoma, Wilm's tumour, Choriocarcinoma, testicular cancer, and Kaposi's sarcoma

Bleomycin◦ Mechanism of Action -- Bleomycin binds to DNA and

generate free radicals. CCS DRUG (G2 PHASE)◦   Uses -- Squamous cell carcinoma, œsophageal cancer,

testicular and ovarian cancer, and both Hodgkin's(ABVD) and non-Hodgkin lymphoma(MACOP-B).

◦ Toxicity -- Pulmonary fibrosis, cutaneous toxicity (hyperpigmentation, hyperkeratosis, erythema, ulceration). 

Mitomycin ◦acts as an alkylating agent to decrease DNA

synthesis, increase cross-linking of DNA, and to cause single-strand breakage.

◦Uses -- cervical, colorectal, breast, bladder, and lung cancers.

◦Toxicity -- Hæmolytic/uremic syndrome (due to endothelial damage of the red cells and renal epithelium), pulmonary fibrosis and cardiotoxicity.

Mechanism of Action -- Most normal cells can synthesis the amino acid asparagine.  However, many neoplastic cells lack this capability ,thereby depriving the neoplastic cell of asparagine and thus inhibiting protein synthesis, which leads to cell death by apoptosis.

Uses -- leukæmias.

Toxicity -- Hypersensitivity, However decreases in protein synthesis may lead to insulin deficiency and clotting factor deficiency.

Clinical Note -- methotrexate prior to L-asparaginase increases the cytotoxic activity and side effect

EnzymesL-Asparaginase

Mechanism of Action -- Hydroxyurea inhibits the enzyme ribonucleotide reductase, thereby inhibiting the conversion of ribonucleotide to deoxyribonucleotides.  This inhibits DNA synthesis.  Its actions are specific for the G1 to S phase of the cell cycle.

Uses -- Leukæmias, polycythemia vera (overproduction of erythrocytes), malignant melanoma.  Hydroxyurea is also used in the treatment of sickle cell anæmia to decrease hæmolysis.  This effect is mediated by an increase in the synthesis of hæmoglobin F (probably by a separate mechanism, possibly increased expression of the Hgb F gene).

Hydroxyurea

drug-resistantAcquired drug-resistant models possess multiple drug-

resistance mechanisms. These mechanisms include: (a) decreased intracellular concentration of the drug

characteristic of overexpression of drug transporters; (b) alterations in the drug target such as point mutations or

overexpression of the target; (c) increased detoxification of the drug such as glutathione

conjucation; (d) changes in the repair of DNA damage induced by the

drug (e) alterations in the cell cycle checkpoint such as p27or

p21; (F) changes in the ratio of pro and antiapoptotic BCL-2

family members

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