Chem II: Alkylating Agents Flashcards Preview

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Flashcards in Chem II: Alkylating Agents Deck (30):

Is there an advantage to using both a cell cycle specific drug and a cell cycle non-specific drug in the treatment of a patient with cancer? Explain


Describe the characteristic toxicity of the oxazophorines. Describe two strategies for preventing this characteristic toxicity


The alkylating agents do not have schedule dependent cytotoxicity. Why?


Contrast the mechanisms of action of vincristine and paclitaxel.


Which plant alkaloid is NOT a "spindle poison"?


What are the characteristics of cancer chemotherapeutic agents which might indicate that the drugs would have schedule dependent cytotoxicity?


For the drugs covered in this lecture, indicate which drugs require a dose reduction in the presence of jaundice.


For the drugs covered in this lecture, indicate which drugs require a dose reduction in the presence of renal insufficiency.


Discuss the mechanism of cytotoxicity for the bifunctional alkylating agents.


Alkalating agents bind _____ to _____

Are cell cycle ______


--> DNA drug ________ crosslinks

Alkylate at:

How can resistance occur? (2)

Alkalating agents bind covalently to the DNA

Are cell cycle NON-SPECIFIC


--> DNA drug inter AND intra - strand  crosslinks

Alkylate at: N-7 guanine

How can resistance occur? enhanced DNA repair or binding to sulfur containing molecues (sulfur prevents the alkylation)


what type of reaction does cyclophosphamide undergo and where?


What metabolite is the DNA damaging agent?


How is this drug excreted? What symptoms thus can be seen at high doses?

Cyclophosphamide undergoes a microsomal oxidation reaction in the liver

After a few steps --> phosphamide mustard = DNA damaging agent


Phosphamide mustard and acrolein are excreted by the kidneys --> irritaiton to the GU epithelium --> hematuria and at high doses frank hemorrhagic cystitis




Major side effects (5):

What cancers is it used in (3):

Other drugs (2):

Activation is REQUIRED, P-450 oxidase activity

Could be given orally or IV

Side Effects: myelosuppression, N/V, hair loss, hematuria

(mitigate hematuria via morning administration, frequent urination, hydration)


Used for: breast cancer, non-hodgkin's lymphoma, pediatric malignancy


Other drugs: chlorambucil, melphalan


How do the bis(chloroethyl)amines alkylate?

What drugs does this group include?

What is its functionality?

bis(chloroethyl)amines = cyclophosphamide, mechlorethamine (nirogen mustard), chlorambucil, melphalan



One of the chloromethyl groups binds to the DNA, relatively quickly, the other one binds = bifunctional (more potent than monofunctional)


Alkylation could occur on the same strand (intra) or opposite strands (inter) --> crosslinks --> DNA replication and other DNA functions are impiared

Cytotoxicity is directly proportional to the amount of links formed



potency incomparison to other alkylating agents?

Isomer of what other important alkylating agent?


Ifosfamide is useful to use with what types of cancers? (2)


What is one of its toxicities? How could this be prevented?


What side effect is dose limiting? What are other side effects (4)

Ifosfamide is an isomer of cyclophosphamide

It is monfunction, and only 1/5 the potency of others in the bis-group


Useful in the treatment of sarcomas and testicular cancers that have failed other primary therapy


Dose limiting AE: myelosuppression

Other side effects: hematuria (administered with MESNA to prevent toxic effect on urothelium), N/V, hair loss and at large doses lethargy and confusion


What is the use of MESNA?

MESNA is a dimer in the blood and cells thus not activ, in urine, mesna is a monomer and has the ability to bind metabolites of alkylating agents (acrolein, etc) --> prevents urothelial damage and hematuria that can be seen with some chemotherapy agents such as w/the bis(chloroethyl)amides.


Useful for: ifosfamine, cyclophosphamide



MOA? Mono or bi functional?


AE (4)

What is an important phrophylaxis that must be taken with prolong use?

Useful for treatment of what types of tumors? 


MONOfunctional alkylating agent --> spontaneous hydrolysis to the DNA reactive species --> methylates the DNA and inhibits DNA function and synthesis


AEs: Myelosuppression, N/V, hair loss


When used for a prolog period of time, prophylaxis for PCP pneumonia is required 


Useful in: primary brain tumors - glioblastoma

radiation + temozolomide

adjunct steriods + temozolomide


What are Pt-coordination compounts?

What state is Pt in? what state are the leaving groups in?


How do they differ for other classical DNA alkylating agents?


What compunds does this class include? (3)

NON-classical DNA alkylating agents

COVALENTLY bind to DNA; PT in the 2+ oxidation state (anti-tumor) and mostly in the planar formation

Leaving group are "cis"


Differ from classical alkylating agents since they preferentially bind to N7 position of guanine AND adenine


Includes: cisplatin, carboplatin, oxaliplatin



How are pt alkylating activated?


Bi or mono functional?

The compounds start uncharged/unactive at high concentrations of chloride --> once inside the cell, there concentration of chloride drops --> goes through a series of reactions/aquation that changes its composition --> aquated species covalently binds to DNA to produce cytotoxic intra/inter-strand crosslinks


All Pt(II) coordination compounds form the same DNA adducts




What is it used for (5):

What is burdensome about using cisplatin?

Pharmokinetics / metabolism:


How is resistance formed? (2)


Curative in testicular cancer

also useful in: lung, ovarian, head/neck, bladder CA

Tightly bound to proteins in the plasma, excretion in urine

BURDENSOME- must be used w/hydratiio to prevent kidney damage (can take 30+ mins, plus hydration before/after)

Resistance can form if improved nucleotide excision + repair mxn can excise the link; also sensitive to sulfur



What are cisplatin AEs (5):

What are specific precautions that must be taken with cisplatin? What could be done as a prophylaxis?

What is the dose-limiting SE?



Nephrotoxin and excreted by the kidney! MUST KNOW KIDNEY FUNCTION; dose limitation is renal effect/renal function

Prophylaxis: chloruresis (helps protect kidneys: saline, mannitol diuresis) 

VERY emetogenic 


Hypomagnesemia - replace as indicated

High freq hearing loss (we don't hear at this fre, ok?)


also beware that lots of ppt have co-morbid heart disease, ie-heart dx; so they might not be able to tolerate the fluid overload that is co-administered with cisplatin




What are 3 important difference between cisplatin and carboplatin?

Carboplatin is excreted by the kidneys but NOT nephrotoxic

Myelosuppressio is the dose limitation (not renal fxn!)

Easier to give than cisplatin - ALSO we don't have to give fluid along with the drug thus we can give it to dialysis patients or patients with other co-morbidities


What is carboplatin's relationship with GFR?

How can we calculate dosage?

There is a linear relationship between GFR and carboplatin plasma clearance


Dose = AUC x (GFR+25)





Oxaliplatin is useful for what cancer? (1)

What is the dose-limiting factor?

What are other AEs (5 - 2 unique SE)

Useful for colorectal cancer -doubling surivival in metastatic CA

Myelosuppresion is the dose limiting factor 

AEs: N/V, vein irritant,

acute cold-induced neuropathy (reversible),

chronic sensory neuropathy (mild, rarely disabling, resolved)

first chew phenomenon


What chemotherapy agents are naturally occuring products of plant alkaloids? (3)


Semisynthetic? (1)


Natural: vincristine, vinblastine (periwinkle plant), taxol


Semi-synthetic: Etoposide


What is the effect of natural plant alkaloids on the cell? Are these agents cell cycle specific or non?


..of Etooside?

Vincristine, vinblastine and toxol are cell-specific M-phase and inhibit mitotic spindle formation (vinblastine, vinccristine) or prevent breakdown of miotic spindle (toxol)


Etoposide / VP-16 inhibits topoisomerase II and DNA strand breakage occurs



Cell cycle specific specific at what point?


What is the MOA?


What is its dose limitation? 

When is dose-reduction required?


What is it useful for (3)


What are others?

Cell cycle specific during M-phase --> prevents polymerization of tubulin

Dose limitation: Neuropathy (NO myelosuppresion)

Dose-reduction required for elevated bilirubin due to its exretion via bile


Used for: lymphoma, hodgkin's disease, lymphoblastic leukemia

Others: vinblastine, vinorelbine (lessneurotox, more myleo)




is cell cycle specific during what phase? What does it cause?

When are dose adjustments required?

What are its AEs (7)

What is should be given prior to starting treatment?


Useful for what types of tumors (4):

Cell cycle specifc (M-phase) --> prevents tubulin disassembly

Hepatic metabolism of drug -- thus drug adjustments req with hepatic dysfunction

AEs: myeolsuppression, hair loss, N/V, stomattiis, peripheral sensory neuropathy (PROBLEMATIC!), myalgias, arthralgias


Premedication to prevent allergic rxs to solvent

Useful for: ovarian CA, lung CA, gastroesophageal CA, breast CA



What are other compounds related to paclitaxel (3) and what are their usage?

Docetaxel --> prostate cancer

Albumin bound paclitaxel -- no allergic reactions and LESS myelosuppression, less neuropathy

Cabazitaxel (carboplatin + paclitaxel) -- prostate cancer!



Cell cycle specific during what phrase? what effect does this have on the cell?


What is the dose limiting factor?

AEs (3):

What effect can this drug have at higher doses?


When are dose reductions required (2):


What is it useful for? 



Cell cycle specifc during G1-S phase--> targes topoisomerase II and produced DS-DNA breaks

AEs: N/V and hair loss

Dose limitation: myelosuppression

**LEUKEMOGENIC at total doses > 2 gm/M^2**

Dose reductions required for: renal and hepatic dysfunctions 

Good for: TESTICULAR, lung CA and lymphomas


What are the three big drugs used for testicular cancer?!