CHAPTER 10ANTINEOPLASTIC AGENTS

Chapter overview:

Chemistry, use, metabolism and adverse effects of alkylating agents, antibiotics, natural products, antimetabolites and tyrosine kinase inhibitors in the treatment of cancer

ACS : cancer as a group of diseases characterized by uncontrolled growth and the spread of abnormal cells that left untreated may lead to death.

Neoplasm which is the uncontrolled growth of new tissue, the product of which is known as tumor.

Malignant tumors are invasive and moving to distant locations known as metastasis.

Chemotherapy refers to drugs that are used to kill cells and includes both antibiotics and agents used in the treatment of cancer, but it is often used to refer exclusively to anticancer agents also known as antineoplastics.

The approach to treatment depends on the so called stage, the commonly used is the TNM system.

Stage 0 to IV

ALKYLATING AGENTS Are a class of drugs that are capable of forming

covalent bonds with important biomolecules.

Major target of drug action are the nucleophilic groups present on DNA especially on position 7 of guanine)

Alkylation of DNA is thought to lead to cell death.

Potential mechanisms of cell death include activation of apoptosis caused by p53 activation and disruption of the template function of DNA.

ALKYLATING AGENTS

Possibility of cancer cells resistance to alkylating agents because cancer cells have dysfunctional p53 thus apoptosis does not occur.

General mechanism for alkylation involves nucleophilic attack of DNA and RNA.

ALKYLATING AGENTS

Mechanisms by which cells may become resistant to these agents are thought to be similar which include: decreased cellular uptake Increased inactivation by glutathione Increased DNA repair processes Decreased drug activation

ALKYLATING AGENTS

Alkylating agents are thought to be effective from Go-M

Therefore cell cycle non specific (CCNS)

Toxicities are similar with various agents Myelosuppression GI disruption – nausea and vomiting As these cells are highly proliferative

making them susceptible to the effects of alkylating agents

ALKYLATING AGENTS – NITROGEN MUSTARDS

ALKYLATING AGENTS – NITROGEN MUSTARDS Investigation of sulfur mustard has

led to a discovery that it possess antineoplastic properties

Mustards such as mechlorethamine are dialkylating agents. Highly reactive thus oral administration

is not possible, necessitating direct injection into the tumor cell.

ALKYLATING AGENTS – NITROGEN MUSTARDS In cases of extravasation, antidote

sodium thiosulfate is needed. To decrease the incidence of kidney

and bladder toxicity – the sulfhydryl containing mesna is administered.

ALKYLATING AGENTS-ORGANOPLATINUM COMPOUNDS

Organometallic compounds based on platinum that play a central role in many cancer protocols

CISPLATIN Inhibit cell division Associated with nephrotoxicity and

neurotoxicity that is dose-limitingResistance is the same as with other chemotherapeutic agents.

ALKYLATING AGENTS – INDIVIDUAL AGENTS: MECHLORETHAMINE HYDROCHLORIDE (NH2, MUSTARGEN)MECHANIS

M OF ACTION

PREPARATION INDICATION ADVERSE EFFECTS

OTHERS

10 mg vial for IV HODGKIN’S LYMPHOMA Dose-limiting myelosuppression & nv

Significant risk of extravasation

Part of MOPP regimen : Addn’l: Alopecia

M – mechlorethamineO – (Oncovin) Vincristine

Azoospermia, amenorrhea

Topical

P – ProcarbazineP – Prednisone

Treatment of MYCOSIS FUNGOIDES- rare CA but most common T-cell lymphoma

Hyperuricemia, secondary cancers

ALKYLATING AGENTS – INDIVIDUAL AGENTS: CHLORAMBUCIL

PREPARATION INDICATION ADVERSE EFFECTS

OTHERS

2 mg tablet for oral administration

(75% well absorbed foollowing PO)

HODGKIN’S LYMPHOMA & CLL , in combination with prednisone & as a single agent.

Dose-limiting myelosuppression- leucopenia and thrombocytopenia.Nausea, vomiting

Others: hyperuricemiaAzoospermiaAmenorrheaSeizuresPulmonary fibrosisSkin rash

Eliminated via kidneys

Metabolism via CYPActive metabolite – phenylacetic acid-nitrogen mustard

Resistance – same as mechlorethamine

ALKYLATING AGENTS – INDIVIDUAL AGENTS: MELPHALANPREPARATION INDICATION ADVERSE

EFFECTSOTHERS

2 mg tablet50 mg vial

Multiple MyelomaBreast CAOvarian CAHigh dose therapy in bone marrow transplant

Myelosuppression, nausea, vomiting, hypersensitivity, skin rash, alopecia

Resistance – same as mechlorethamine

Inactivated by water to give hydroxy metabolites

Elimination thru the feces

ALKYLATING AGENTS – INDIVIDUAL AGENTS: Cyclophosphamide

PREPARATION INDICATION ADVERSE EFFECTS

OTHERS

25 mg and 50 mg tablet

Vials: 100-, 200-, 500-,1000- , and 2000mg vials

Non Hodgkin’s lymphomaCLLBone & soft tissue sarcomaOvarian CARhabdomyosarcomaNeuroblastoma,Wilms tumor

Myelosuppression- leucopenia, Bladder toxicity – hemorrhagic cystitis (tx: inc water intake and Mesna)

AmmenorrheaAlopeciaCardiotoxicity Inappropriate secretion of anti diuretic hormone ,secondary CA

Resistance – same as other alkylating agent

Well absorbed orally

ALKYLATING AGENTS – INDIVIDUAL AGENTS: Ifosfamide PREPARATION INDICATION ADVERSE

EFFECTSOTHERS

Vials: 1-3gNon Hodgkin’s & Hodgkin’s lymphoma soft tissue sarcomaGerm cell tumorsSmall cell lung CANon small cell lung CA CA of head & NeckBladder CACervical CAEwing sarcoma

MyelosuppressionBladder toxicityN,VAmmenorrheaAlopeciaInappropriate secretion of anti diuretic hormone

Neurotoxicity is asso with production of chloroacetaldehyde presents as confusion, seizure, weaknessm hallucination, coma

Resistance – same as cyclophosphamide

Eliminated in the urine

ALKYLATING AGENTS – INDIVIDUAL AGENTS: BUSULFANPREPARATION INDICATION ADVERSE

EFFECTSOTHERS

2 mg tabVials: 10ml

CMLHigh dose tx for refractory leukemia with BM Transplant

MyelosuppressionNausea, vomitingInterstitial pulmonary fibrosis “ BUSULFAN LUNG” ( 1-10 years post tx)

MucositisSkin rashImpotenceAmenorrheainfertility., etc

Well absorbed orally

Metabolism – liver, metabolites excreted in the urine

ALKYLATING AGENTS – INDIVIDUAL AGENTS: ThiotepaPREPARATION INDICATION ADVERSE

EFFECTSOTHERS

Vials: 15mg Bladder CAOvarian CABreast CA

MyelosuppressionNausea, vomiting

MucositisSkin rashImpotenceAmenorrheainfertility., etc

ALKYLATING AGENTS – INDIVIDUAL AGENTS: CisplatinPREPARATION INDICATION ADVERSE

EFFECTSOTHERS

Vials: 10 and 50 mg vial

Non hHodgkin’s lymphomaTesticular CABladder CAOvarian CACA of Head & neck

Nephrotoxicity – increased BUN and CreatinineNeurotoxicity

MyelosuppresionNauseaVomitingAlopeciaOtotoxicityMyocardial infectionThrombotic events

ALKYLATING AGENTS – INDIVIDUAL AGENTS: CarboplatinPREPARATION INDICATION ADVERSE

EFFECTSOTHERS

Vials: 50mg, 150mg, 450mg

Ovarian CABladder CAHead and neck CASmall cell lung CANSCLC

MyelosuppressionRenal toxicityN,vPeripheral neuropathy

ALKYLATING AGENTS – INDIVIDUAL AGENTS: OXALIPLATIN

TX of ovarian CA Metastatic colorectal CA Early colon CA in combination with 5

FU/leucovorin SE: neurotoxicity▪ Others:▪ Nausea, vomiting, myelosuppression,

hypersensitivity

ALKYLATING AGENTS – INDIVIDUAL AGENTS: CARMUSTINE

For brain tumor, Hodgkin’s, non Hodgkin’s, multiple myeloma

Pulmonary toxicity Hepatotoxicity

ALKYLATING AGENTS – INDIVIDUAL AGENTS: PROCARBAZINE

Oral tx in Hodgkin’s disease (part of MOPP)

Crosses blood-brain barrier N,v, flu like symptom

STREPTOZOCIN Metastatic islet cell CA of the pancreas,

colon CA, Hodgkin’s disease Renal toxicity

ALKYLATING AGENTS – INDIVIDUAL AGENTS: DACARBAZINE

Hodgkin’s disease, malignant melanoma, neuroblastoma, soft tissue sarcoma

SE: leukopenia, thrombicytopenia, photosensitivity

ALTRETAMINE Second-line treatment for ovarian CA