CHAPTER 10 ANTINEOPLASTIC AGENTS
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