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Pharmacology > Cancer IIIA - Alkylating Agents > Flashcards

Cancer IIIA - Alkylating Agents Flashcards

1
Q

Alkylating Agents:

  1. Share capacity to contribute alkyl groups: chemotherapeutic effects are directly related to?
  2. Strong ___ by formation of _______ ____ intermediate can now attack nucleophilic moieties such as?
  3. Forms ____ linkages.
A

Alkylating Agents:

  1. Chemotherapeutic effects are directly related to alkylation of DNA
  2. Strong electrophiles by formation of carbonium ion intermediate can now attack nucleophilic moieties such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups
  3. Forms covalent linkages
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2
Q

Alkylating Agents:

  1. ___ of guanine is particularly suceptible to alkylation as well as what of adenine? Cytosine? Guanine?
  2. Alkylation of guanine leads to an? What does this change? Ultimate result?
A

Alkylating Agents:

  1. N7 of guanine is susceptible; N1/N3 of adenine; N3 of cytosine; O6 of guanine
  2. Alkylation of guanine leads to an enol tautomer; this changes base pairing; G now pairs with T and the ring is destabilized leading to opeining or depurination by excision
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3
Q

Alkylating Agents:

  1. What occurs with a second alkylating agent?
  2. The final result is?
  3. Acute effects act against? (in dividing tissue_
  4. What occurs in non-dividing cells? What occurs in cells with mutant/absent p53?
A

Alkylating Agents:

  1. Second alkylation leads to cross linking of two nucleic acid chains or nucleic acid to protein
  2. Final result is cell cycle arrest and apoptosis
  3. Acute effects agains rapidly proliferating tissues
  4. In non-dividing cells, DNA damage leads to activation of p53-dependent checkpoint. Cells with mutant/absent p53 are resistant to alkylating drugs
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4
Q

Alkylating Agents:

  1. Difference between bifunctional and monofunctional reagents?

Mechanisms of Resistance:

  1. Decreased uptake of _____ transported drugs. Example?
  2. Increased incracellular concentrations of _____ substances (such as ____) which scavenge ____.
A

Alkylating Agents:

  1. Bifunctional = cytotoxicity predominates; monofunctional = greater capacity for mutagenesis and carcinogenesis

Resistance:

  1. Decreased uptake of actively transported drugs; mechlorethamine and melphan
  2. Increased concentration of nucleophilic substances ( glutathione) which scavenge electrophiles
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5
Q

Alkylating Agents:

Mechanisms of resistance:

  1. Increased activity of ____ ____ pathways: increased activity of ___ ___ pathway, resistance to most ____ and ____ adducts; increased ___ activity: resistance to BCNU, _____, and busulfan
  2. Increased rates of metabolism of _____ and ____ to inactivate keto and carboxy metabolites by ____ ___.
A

Alkylating Agents:

Mechanisms of resistance:

  1. Increased activity of DNA repair pathways: increased activity of nucleotide excision pathway, resistance to most chloroethyl and platinum adducts; increased AGT activity: resistance BCNU, procarbazine, and busulfan
  2. Increased rates of metabolism of cyclophosphamide and ifosfamide to inactive keto and carboxy metabolites by aldehyde dehydrogenase
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6
Q

Alkylating Agents:

To reverse resistance: treatment with drugs to deplete _____ levels, __-benzylguanine (inactivates ___) and ethacrynic acid (inhibits ____ transferases). Methylation of the _____ promoter often identifies suceptibility of ____ to treatment

A

Alkylating Agents:

To reverse resistance: treatment with drugs to deplete glutathione levels, O6-benzylguanine (inactivates AGT) and ethacrynic acid (inhibits glutathione transferases). Methylation of the MGMT promoter often identifies suceptibility of gliomas to treatment

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7
Q

Alkylating Agents:

Toxicities:

  1. _____ _____ toxicity leads to ____
  2. Suppression of ____
  3. Mucosal toxicity leads to?
  4. Neural toxicity causes?
A

Alkylating Agents:

Toxicities:

  1. Bone Marrow toxicity leads to myelosupression
  2. Suppression of immunity
  3. Mucosal tox –> oral ulceration and intestinal denudation (wearing away) and can lead to bacterial sepsis
  4. Neural tox –> N/V
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8
Q

Alkylating Agents:

Toxicities:

  1. Effects on reproduction?
  2. What other toxicity?
  3. After months or years can lead to what two things?
A

Alkylating Agents:

Toxicities:

  1. Reproduction: amenorrhea and azoospermia
  2. Alopecia
  3. Months/years: pulmonary fibrosis and leukemogenesis (induction of leukemia)
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9
Q

Nitrogen mustards:

MOA:

Formation of _____ ______ ions capable of forming _____ bonds with macromolecules. The primary result is the formation of bi-functional ____ between complementary strands of DNA, between DNA and ____, and _____ of proteins.

A

Nitrogen mustards:

MOA:

Formation of chloroethyl carbonium ions capable of forming covalent bonds with macromolecules. The primary result is the formation of bi-functional crosslinks between complementary strands of DNA, between DNA and proteins, and alkylation of proteins

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10
Q

Nitrogen mustards:

MOA:

Early compounds were initially developed for chemical ____ and are vesicants (produce ____) they are now used in the treatment of ____

A

Nitrogen mustards:

MOA:

For chemical warfare and are vesicants (produce blisters) they are now used in the treatment of lymphomas

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11
Q

Nitrogen mustards:

  1. Administration? Why?
  2. Predominant action is the formation of DNA ____ and _____ and DNA-protein _____
  3. Primary site of alkylation? And the ___ position of an adjacent ___ or ___.
A

Nitrogen mustards:

  1. IV due to vesicant properties
  2. Predominant action is the formation of DNA interstrand and intrastrand and DNA-protein crosslinks
  3. Primary site: guanine N-7 position; and the N-7 position of an adjacent guanine or adenine
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12
Q

Nitrogen mustards:

  1. Alkylated bases may undergo what kind of step? This is subsequently removed by? Causes?
  2. Major toxicities?
A

Nitrogen mustards:

  1. May undergo a ring opening step; subsequently removed by repair enzymes; generates DNA breaks
  2. Tox: N/V and myelosupression as well as potential menstrual irregularities (not permanent) however males may become sterilized
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13
Q

Cyclophosphamide:

  1. What category? One of the most ____ of the kinds.
  2. Requires metabolic activation to? Where?
  3. Administration?
A

Cyclophosphamide:

  1. One of the most stable nitrogen mustards
  2. Requires metabolic activation to 4-OH-cyclophosphamide in the Liver
  3. Oral or IV
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14
Q

Cyclophosphamide:

MOA:

  1. DNA ____ similar to nitrogen mustard.
  2. Peak levels of damage when?
  3. Major toxicity?
A

Cyclophosphamide:

MOA:

  1. DNA crosslinking similar to nitrogen mustard
  2. Peak levels of damage 6-12 hours
  3. Toxicity: myelosupression, alopecia, N/V, and hemorrhagic cystitis
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15
Q

Cyclophosphamide:

  1. How does hemorrhagic cystitis occur? With administration of ____. Explain.
  2. What are the two inactive metabolites in the metabolism of cyclophosphamide?
  3. What are the toxic metabolites of cyclophosphamide?
A

Cyclophosphamide:

  1. Administration of mesna: cyclophosphamide converted to urotoxic metabolites such as acrolein. It neutralizes these by binding through its sulfhydryl moieties and increases urinary exretion of cysteine
  2. Inactive metabolites: 4-ketocyclophosphamide and carboxyphosphamide
  3. Active: Acrolein and phosphoramide mustard
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16
Q

Melphalan:

  1. Linked to what amino acid?
  2. Transported by what uptake system?
  3. Derivative of?
A

Melphalan:

  1. Linked to L-phenylalanine
  2. Transported by leucine transport uptake system
  3. Derivative of nitrogen mustard
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17
Q

Melphalan:

  1. Peak DNA damage time?
  2. Major toxicity?
  3. Infrequent toxicity? What 3 things do not occur?
A

Melphalan:

  1. Peak damage time: 6-12 hour delay
  2. Major toxicity: hematological
  3. Infrequent: N/V; Not occuring: alopecia, hepatic, and renal toxicities
18
Q

Chlorambucil:

  1. Causes increased _____ which allows for what administration?
  2. MOA is similar to?
  3. Minor toxicity?
  4. Major toxicities?
A

Chlorambucil:

  1. Caused increased toxicity which allows for oral administration
  2. MOA similar to nitrogen mustard
  3. Minor tox: mild myelosupression
  4. Major tox: GI, hepatotoxicity, and menstrual irregularities
19
Q

Alkyl Sulfonates:

Drug?

A

Alkyl Sulfonates:

Busulfan

20
Q

Busulfan:

  1. Length of internal alkyl chain?
  2. Major mechanism of action is _____ of DNA and ____.
  3. Alkyl chains of what length lose activity?
  4. C8/C9 analogs however have ___-___ activity and DNA ____ activity is recovered
  5. Major toxicity? Prolonged use can lead to?
A

Busulfan:

  1. Length of internal alkyl chain: C=4
  2. Major MOA is crosslinking of DNA and protein
  3. Alkyl chains of C6/C7 lose activity
  4. C8/C9 analogs however have anti-tumor activity and DNA crosslinking activity is recovered
  5. Major tox: myelosupression and prolonged use can lead to loss of bone marrow function
21
Q

Nitrosoureas:

2 moieties?

A

Nitrosureas:

a. Chloroethyl notrosoureas
b. Methylnitrosoureas

22
Q

Nitrosoureas:

  1. Examples of chroloethyl nitrosoureas?
  2. Example of methylnitrosourea?
A

Nitrosoureas:

  1. Chloroethyl nitrosoureas: BCNU-carmustine, CCNU-Lomustine, Methyl-CCNU-semustine
  2. Methylnitrosourea: Streptozotocin
23
Q

Chloroethyl Nitrosoureas:

  1. Highly _____ and readily cross the ____ ____ ___.
  2. CCNU decompose to produce an _____ moiety which can further decompose to a ____ ____ ion that produces?
  3. Another breakdown product is an ____ that reacts primarily with ____ residues in proteins.
A

Chloroethyl Nitrosoureas:

  1. Highly lipophilic and readily cross the blood brain barrier
  2. CCNU decomposes to produce an alkylating moiety which can further decompose to a chloroethyl-carbonium ion that produces DNA intrastrand and interstrand crosslinks
  3. Another breakdown product is an isocyanate that reacts primarily with lysine residues in proteins
24
Q

Chloroethyl Nitrosoureas:

  1. The alkylating properties are responsible for ____ activity. ______, which does not carbamoylate, retains _____ activity.
  2. Adverse toxicities are?
  3. Delayed ____ failure has been observed in children given ____. What else is common?
A

Chloroethyl Nitrosoureas:

  1. The alkylating properties are responsible for antitumor activity. Chlorozotocin, which does not carbamoylate, retains antitumor activity
  2. Adverse toxities: severe delayed myelosuppression (at about 4 weeks) caused by the carbamoylating breakdown products
  3. Delayed renal failure has been observed in children given MeCCNU. Common: N/V
25
Q

Streptozotocin:

  1. High affinity for what cells?
  2. Useful in treatment of what?
  3. Administration?
A

Streptozotocin:

  1. High affinity for cells of the islets of langerhans
  2. Useful in the treatment of pancreatic islet cell carcinoma
  3. IV administration
26
Q

Streptozotocin:

  1. Metabolic activation?
  2. MOA?
  3. Toxicity?
A

Streptozotocin:

  1. Does NOT require metabolic activation
  2. MOA: Methylation of DNA at guanine O-6
  3. Tox: N/V, hepatic, and renal toxicity; hematological toxicities in 20% of patients. Compound is mutagenic and may be carcinogenic
27
Q

Triazenes-Methylhydrazines:

Drugs?

A

Triazenes-Methylhydrazines:

a. Dacarbazine (DTIC)
b. Procarbazine

28
Q

Dacarbazine:

  1. Activation where? Acts as a ____ agent.
  2. What is the active metabolite? Kills cells in ____ phases of cell cycles
  3. Resistance due to removal of ____ groups from ______ of DNA by ___.
  4. Toxicity?
A

Dacarbazine:

  1. Activation in the liver; acts as a methylation agent
  2. Active metabolite = monomethyl triazeno metabolite (MTIC); Kills cells in ALL phases of cell cycle
  3. Resistance due to removal of methyl groups from O6-guanine of DNA by AGT
  4. Toxicity: N/V, myelosuppression, chills, fever, and malaise
29
Q

Procarbazine:

  1. MOA: DNA _____. Converted to active metabolism by ____
  2. Causes?
  3. Inhibition of?
A

Procarbazine:

  1. MOA: DNA methylation. Converted to active metabolism by CYP
  2. Produces DNA strand breaks, chromatid breaks, and translocations
  3. Inhibition of DNA, RNA, and protein synthesis
30
Q

Procarbazine:

  1. Administration?
  2. Treatment?
  3. Toxicity?
A

Procarbazine:

  1. IV or Oral
  2. Treat Hodgkin’s disease and brain tumors
  3. Toxicity: myelosuppression, N/V, highly carcinogenic/mutagenic/teratogenic, causes infertility (especially in males)
31
Q

Platinum Coordination complexes:

3 drug examples.

A

Platinum coordination complexes:

a. cisplatin
b. carboplatin
c. oxaliplatin

32
Q

Platinum coordination complexes:

  1. Which is the parent compound? Another name?
  2. Carboplatin is a ___ generation.
  3. Cisplatin and carboplatin treat?
  4. Oxaliplatin treats?
A

Platinum coordination complexes:

  1. Cisplatin is the parent compount; DDP
  2. Carboplatin is a second generation drug
  3. Cisplatin and carboplatin: genitourinary cancer and lung cancer
  4. Oxaliplatin: colon cancer
33
Q

Platinum coordination complexes:

  1. The drugs them selves are _____ DNA reactive.

2 Must undergo?

  1. The adducts formed with DDP and DNA are identical to those formed with ______ and DNA
A

Platinum coordination complexes:

  1. Drugs themselves are NOT DNA reactive
  2. Must undergo sequential aquation
  3. The adducts formed with DDP and DNA are identical to those formed with Carboplatin and DNA
34
Q

Platinum coordination complexes:

  1. Intra versus interstrand adduct %?
  2. DNA _____ crosslinks also form but they are NOT a determinant of ____.
  3. How can the interstrand and intrastrand crosslinks be excised?
A

Platinum coordination complexes:

  1. IntRAstrand adducts >95%; intERstrand adducts <5%
  2. DNA Protein crosslinks also form but they are NOT a determinant of cytotoxicity
  3. The crosslinks can be excised by DNA repair mechanisms - specifically Nucleotide excision repair
35
Q

Platinum coordination complexes:

  1. DNA adducts inhibit?
  2. DNA adducts lead to?
  3. Administration?
  4. Enter cells how?
A

Platinum coordination complexes:

  1. DNA adducts inhibit DNA replication and transcription
  2. Adducts lead to breaks and miscoding, leading to activation of p53 and mismatch repair proteins and initiation of apoptosis
  3. IV
  4. Enters cells by diffusion AND an active Cu2+ transporter
36
Q

Platinum coordination complexes:

  1. Carboplatin shares cross-resistance with? What analogs dont?
  2. When does resistance occur? (overexpression of?)
  3. Resistance to cisplatin, but not _____, partly mediated through ______ _____
A

Platinum coordination complexes:

  1. Carboplatin shares cross resistance with cisplatin but NOT oxaliplatin and other tetravalent analogs
  2. Resistance occurs with overexpression of nucleotide excision repair
  3. Resistance to cicplatin, but not oxaliplatin, partly mediated through the mismatch repair (MMR)
37
Q

Platinum coordination complexes:

  1. Major Cisplatin toxicity?
  2. How can it be prevented?
  3. What can reduce cisplatin toxicity?
  4. Carboplatin in comparison?
  5. Other toxicity?
A

Platinum coordination complexes:

  1. Cisplatin: nephrotoxicity
  2. Prevented by adequate hydration and diuresis
  3. Reduce tox with thiol-containing amifostine
  4. Carboplatin has LESS nephrotoxicity
  5. Other: ototoxicity, N/V, mild myelosuppression, and electrolyte imbalance
38
Q

Platinum coordination complexes:

  1. Higher dose of cisplatin may cause?
  2. Major toxicity of oxaliplatin?
  3. Oxaliplatin may induce a unique acute _____ that is exacerbated by exposure to?
A

Platinum coordination complexes:

  1. Higher dose: progressive peripheral motor and sensory neuropathy
  2. Oxaliplatin: peripheral neuropathy
  3. Oxaliplatin may induce a unique acute neurotoxicity that is exacerbated by exposure to cold temperature
39
Q

Combination RX for testicular cancer:

  1. RX of local disease without metastasis?
  2. Combo = ___
A

Combination RX for testicular cancer:

  1. W/o metastasis: surgery (w/ or w/o radiation)
  2. Combo = PVB
40
Q

Combination RX for testicular cancer:

PVB

3 drugs? Phase specificity/role? Days?

A

Combination RX for testicular cancer:

PVB:

a. Cisplatin: day 1-5; draw non-dividing tumor cells into actively cycling pool
b. Vinblastine: day 1-2; M phase specific
c. Bleomycin: days 2, 9, 16; G2 phase specific

41
Q

Implantable HAI pump with a catheter in the hepatic artery:

  1. Liver metastases are mainly supplied by what artery?
  2. Ideal drug for hepatic arterial infusion (HAI)?
  3. Why is this a good drug?
A

Implantable HAI pump with a catheter in the hepatic artery:

  1. Supplied by hepatic artery
  2. Drug: Floxuridine
  3. Good bc of its short half life, steep dose response curve, high total body clearance, and high hepatic extraction
42
Q

Implantable HAI pump with a catheter in the hepatic artery:

  1. Response rates in comparison to systemic chemo alone?
  2. What other advantage?
  3. High hepatic extraction of FUDR limits?
  4. Toxicity?
A

Implantable HAI pump with a catheter in the hepatic artery:

  1. Response is greater than systemic chemo alone
  2. Survival advantage
  3. Limits systemic side effects
  4. Tox: biliary and GI ulcers

Pharmacology (24 decks)

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