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PH3502-Chemotherapy and selective toxcitiy > Lec 17- alkylating agents > Flashcards

Lec 17- alkylating agents Flashcards

1
Q

Alkylating agents

A
  • Largest class of anti-neoplastics
  • General properties/mechanism
    • All are electrophilic molecules that covalently modify nucleophilic molecules in cells
      • DNA most important adduct (N7 and O6 of Guanine) for anticancer properties
  • General types of alkylating agents
    • Monofunctional
      • Cause single strand DNA breaks
    • Bifunctional
      • Inhibit DNA replication and transcription by cross-linking DNA
    • Subtypes
      • Nitrogen mustards
      • Nitro-ureas
      • Cis-platinum compounds
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2
Q

Alkylating agents

Sub-types

A
  • Nitrogen mustards
  • Nitroso-ureas
  • CIS platinum compounds
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3
Q

Concept alkylation agents

A
  • What to alkylate
  • Busulfan- has a methyl sulphonic acid leaving the group- this is equivalent of having chlorine (We can’t use the chlorinated version as it is too toxic)
  • Must have a nucleophilic centre
  • N is nucleophilic, the drug is electrophile, results in alkylation
  • Methane sulfonic acid= leaving group = CI atom
  • With an alkylating agent on 2 separate sides we can cross-link DNA- causing a blockage of DNA transcription
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4
Q

Concept Alkylation

A
  • Busulfan= alkylation
  • 2 leaving groups
  • Selective toxicity
  • 5-FU- fluorouracil
  • Anti-metabolite
  • Fluorine= no leaving group mimic H
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5
Q

Complementary base pairs hold the DNA strands

A
  • For anti-virals, we either modify the base or sugar- mimic nucleoside
  • Base- was an alkylating agent can work
  • Chemotherapy- interact with nucleoside
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6
Q

Nitrogen mustards

A
  • Compound
  • Mechlorethamine (mustargen) R=Me
  • Hodgekins/lymphomas and chronic leukaemias
  • MOPP (Mechlorethamine, vincristine, Oncovin, Procarbazine, Prednisone)
  • MOPP regimen
  • This agent is not just alkyl group and chlorine- it also has an N which increase efficacy
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7
Q

Mechlorethamine (Mustargan)

A
  • Mustargan= prototype for the mustards (and other alkylating agents) because of its spectrum of activity
  • Toxicities / Mechanism of action
  • Highly unstable and reactive- still in use in combination therapy, MOPP 80% response, >50% cure
  • Toxicity: nausea and vomiting (N&V). Dose limiting toxicity (DLT) is bone marrow suppression, WBC, esp granulocytes
  • Max suppression at 10-12 days, recovery around 42 days
  • ADME: t1/2 less than 30 minutes, admin in free flowing catheter
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8
Q

Mechlorethamine (mustargan) R=Methyl

Analogs

A
  • Chlorambucil
  • Melphalan, multiple myeloma
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9
Q

Chlorambucil

A
  • Chronic lymphocytic leukemia
  • Malignant lymphomas
  • Cumulative bone marrow toxicity
  • Made aromatic- reduction in toxicity
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10
Q

SAR optimisation

A
  • Replace Me as too reactive- too toxic
  • Use amino acid, Phe = Phenylalanine- as in Melphalan
    • Again reduce toxicity
  • arylated acid= chlorambucil
  • Steroid, uracil and phosphamide- cyclophosphamide
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11
Q

MOA of mustards

A
  • Nitrogen is nucleophillic and removes chlorine to form an aziridine structure
  • Aziridine structure is more reactive than chlorine on its own
  • Guanine has nucleophillic N which reacts with the aziridine structure
  • The removal of the 2nd chlorine atom- form another azirine structure
    • This one reacts with the other guanine base to cross-link the DNA
    • Driven by an SN2 reaction
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12
Q

MOA part 2

A
  • SN2 reaction
  • Nucleophillic centre
  • DNA cross-linked
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13
Q

Mustard: replacement of Me by phosphamide: Cyclophosphamide (cytoxan)

A
  • Use- malignant lymphomas, various carcinomas, most widely used alkylating agent
  • Efficacy: CMF regime increase 7 yr survival from 31% to 49%
  • c= Cyclophosphamide
  • M= MTX
  • F= Fluorouracil
  • MOA= activated by CYP450 pro-drug
  • Toxicity: better bone marrow recovery better than mustargen
  • Treatment: max 10-12 days, recovery 21 days
  • ADME- may be administered parenterally, in a large range of doses. Resistant cells may have aldehyde oxidase
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14
Q

Cyclophosphamide activation

A
  • Activated by P450
  • Oxidise molecule and add a hydroxy group
  • The aldehyde is then formed
  • Allowing cytotoxic to be formed
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15
Q

Nitrosoureas

A
  • Bis-chloro-nitrosurea (BCNU)- lose nitrogen (forming a positive charge) and attacks anything nucleophillic- this can attack most things with electron density (not just nucleophillic centres)
  • Chloroethylcyclohexylnitrosurea -Lomustine (CCNU)
  • BCNU + CCNU
    • Both used for brain tumour, hodgkin’s disease, melanoma
      • lipid soluble (CNS active)
      • O6 of Guanine preferred alkylating site, O alkylation (Mustard N alkylation)
      • Teratogenic
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16
Q

MOA- nitrourea

A
  • They lose isocynate
  • Then lose N2 and H20
  • This leaves group with positive charge and chlorine
    • Positive charge attacks one base first
    • Chlorine alkylates the other base
      • This cross-links the DNA
17
Q

Nitroso-Ureas

A
  • Mustards: N-alkylation of base (heterocyclic template), SN-2
  • Nitrosoura: O alkylation, SN-1, different cross-linking
  • Carmustine: 2 reactive chlorine leaving groups as mustards
  • Lomustine: initially 1 reactive site
    • Lipophilic cyclo-hexyl group, brain penetration
    • Activation: loss of nitrogen- N2
    • 2 reactive sites for co-valent reaction= cross-linking
18
Q

BCNU (Carmustin)

A
  • Use: primary glioblastoma (with surgery and radiation can increase live span from 20 weeks to 50)
  • Toxicity: High, max 28 days: recovery 42 days
  • ADME: administered by injection
  • Very lipophilic and low ionization at physiological pH- risk of hematological toxicity persist due to storage in the liver
19
Q

Transfer of Me group-alkylation- methylation

Temozolomide

A
  • Liver activation results in diazomethane which transfers one methyl group onto the DNA
20
Q

Temozolomide

A
  • Discovered at Aston derived from dabcarbazine
  • Metabolic activation, dose 200mg/m2 daily for 5 days
  • Brain tumour, glioma
  • t1/2= 1.2h, orally administered Cmax- 1h
  • High CNS penetration
  • Active metabolute MTIC
  • 5-amino-imidazole-4-carboxamide AIC, is natural constituent of urine
  • Methylation of N3 adenine, O6 of guanine
21
Q

CIS- platinium compounds

A
  • Cis-platin lead structure
  • Least stable chelate
  • Most reactive
  • Most Toxic
  • Platinum creates a double positive compound- 2 DNA bases form a chelate on the Pt
    • Not cross-linking
  • Any change from cis-platin reduce toxicity
22
Q

CIS-Platin

A
  • Use- most used in combination therapy- 5-FU
  • Efficacy: testicular tumour 85% curative
    • =first line drug for of colon cancer, combination therapy
  • Toxicity: nephrotoxicity, hearing loss at high end
  • ADME: Administrated i.v. after 1-2L saline and mannitol
  • Analog: Carboplatin, Oxaliplatin
23
Q

Alkylating agents- summary

A
  • The largest class of antineoplastic drugs
    • Nitrogen mustards
    • Nitrosoureas
    • Platinum compounds
  • All are electrophilic compounds that react with DNA
    • SN2: Nitrogen Mustards
    • SN1: Nitrosoureas
  • Toxicities vary depending on the particular compound
    • Many have severe bone marrow suppression
    • Platinum compounds tend to show more renal toxicities
24
Q

In-vitro Assay

A
  • New alkylation agents
  • More no than yes
  • Growth factors (hormone) antagonists
  • Yes, must be specific
  • Gastrin: stomach, brain cancer, Cholecystokinin for colon, pancreatic cancer
  • Measure cytotoxicity
    • MTT assay
    • Measure proliferation, cell counting
25
Q

In vitro inhibition of growths

A
  • Inhibition of growth at low concentration
  • Selectivity for particular cell line
  • MIA PACA
  • Miapaca is a human pancreatic carcinoma cell line
  • Desired: IC50 in nonmolar range
  • Selective for particular cell line
26
Q

In Vivo test

A
  • Allograft study: transplant solid tumour
    • Analyse volume of tumour over 2-4 weeks
    • Mouse (Murine) tumour for mice
  • Xenograft study: Transplant human tumour into immunosupressed mouse, nude mice
    • Test a brain tumour in the flank on mouse
    • Model with limitations

PH3502-Chemotherapy and selective toxcitiy (21 decks)

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