alkylating agent Nitrogen mustard IV only - subcutaneous cuases necrosis Use arterial supply that goes to tumor HL = min - very fast Adverse effects Acute - N/V Delayed - decreased blood counts, moderate with most doses Primary use: hodgkins lymphoma (part of MOPP)

alk agent Oral or IV Nitrogen mustard pro-drug - activated by host metabolism Used for many leukemias and lymphomas AE Acute - N/V Delayed - bone marrow depression Alopecia Sterile hemorrhagic cyctitis - signiture effect A metabolite of this drugs is excreted in urine and can damage kidney cells

alk agent Analog of cyclophosphamide IV only It is also a pro-drug but it is not absorbed well Used for Hodgkins and NHL High does ofr bone marrow or stem cell rescue - can be used as ablation therapy Component of ICE (ifosfamide, carboplatin, etoposide) AE Acute: N/V, urinary tract tox More severe bone marrow depression than cyclophosphamide = leukopenia Peripheral neuropathies CNS effects Hallucinations, coma May be due to chloracetaldehyde - metabolite of the drug

alk agent Phenylalanine nitrogen mustard Highly reactive, chemical half life - 50 min Oral absorption inconsistent - primarily given IV Renal excretion Marked myelosuppression Uses: multiple myeloma, myoablative therapy

alk agent Nitrogen mustard Administered orally - once daily Plasma half life - 1.5 hours Was primary drug for CLL - now used only rarely

alk agent Alkylsulfonate Oral, IV for high dose Prior to imatinib, this was the key drug for CML Profound myelosuppression; high dose produces pulmonary fibrosis, hepatic veno-occlusive disease

alk agent (non classic) Nitrogen mustard IV - HL - 30 min Alkylates DNA but inhibits mitotic checkpoints - does two things This makes it good for patients who are resistant to alkylating agents Approved for CLL and indolent B cell NHL Typical alkylating agent adverse effects: N/V, myelosuppresion and mucositis

alk agent (non classic) IV Activated by hepatic metabolism AE: severe N/V, delayed myelosuppresion (dose limiting) Used to treat HL, multiple myeloma

alk agent (non classic) Oral Inhibits DNA, RNA, and protein synthesis; causes strand breaks Higher potential for secondary malignancy than with other alkylating agents Used for H/NHL

antimetabolite Dihydrofolate reductase substrate and inhibitor Tumor cells are more sensitive than normal cells = Greater accumulation in tumor cells Blocks production of bases for DNA synth Orally, IV, intrahtecally (doesn’t cross BBB) Excreted in urine May give high dose - followed by rescue with folinic acid (citrovorin, leucovorin) AE Antifolate effects (bone marrow and GI problems) Chronic use can produce hepatotox - usually this is in patients taking it chronically for RA Resistance - decrased drug accumulation, amplified DHFR, altered DHFR

cancer drugs Flashcards by Matt Zabel

cell cycle specific drugs

Antimetabolites

Topoisomerase inhibitors

Microtubule poisons

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cell cycle non specific drugs

Alkylating agents

Antitumor antibiotics

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alkylating agents (classic)

mechlorethamine

cyclophosphamide

Ifosfamide

melphalan

chlorambucil

busulfam

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alkylating agetns (non classic)

bendamustine

dacarbazine

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mechlorethamine

alkylating agent
Nitrogen mustard
IV only - subcutaneous cuases necrosis
- Use arterial supply that goes to tumor
HL = min - very fast
Adverse effects
- Acute - N/V
- Delayed - decreased blood counts, moderate with most doses
Primary use: hodgkins lymphoma (part of MOPP)

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cyclophosphamide

alk agent
Oral or IV
Nitrogen mustard pro-drug - activated by host metabolism
Used for many leukemias and lymphomas
AE
- Acute - N/V
- Delayed - bone marrow depression
- Alopecia
- Sterile hemorrhagic cyctitis - signiture effect
  - A metabolite of this drugs is excreted in urine and can damage kidney cells

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ifosfamide

alk agent
Analog of cyclophosphamide
IV only
- It is also a pro-drug but it is not absorbed well
Used for Hodgkins and NHL
- High does ofr bone marrow or stem cell rescue - can be used as ablation therapy
- Component of ICE (ifosfamide, carboplatin, etoposide)
AE
- Acute: N/V, urinary tract tox
- More severe bone marrow depression than cyclophosphamide = leukopenia
- Peripheral neuropathies
- CNS effects
  - Hallucinations, coma
  - May be due to chloracetaldehyde - metabolite of the drug

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melphalan

alk agent
Phenylalanine nitrogen mustard
Highly reactive, chemical half life - 50 min
Oral absorption inconsistent - primarily given IV
Renal excretion
Marked myelosuppression
Uses: multiple myeloma, myoablative therapy

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chlorambucil

alk agent
Nitrogen mustard
Administered orally - once daily
Plasma half life - 1.5 hours
Was primary drug for CLL - now used only rarely

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busulfam

alk agent
Alkylsulfonate
Oral, IV for high dose
Prior to imatinib, this was the key drug for CML
Profound myelosuppression; high dose produces pulmonary fibrosis, hepatic veno-occlusive disease

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bendamustine

alk agent (non classic)
Nitrogen mustard
IV - HL - 30 min
Alkylates DNA but inhibits mitotic checkpoints - does two things
- This makes it good for patients who are resistant to alkylating agents
Approved for CLL and indolent B cell NHL
Typical alkylating agent adverse effects: N/V, myelosuppresion and mucositis

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dacarbazine

alk agent (non classic)
IV
Activated by hepatic metabolism
AE: severe N/V, delayed myelosuppresion (dose limiting)
Used to treat HL, multiple myeloma

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procarbazine

alk agent (non classic)
Oral
Inhibits DNA, RNA, and protein synthesis; causes strand breaks
Higher potential for secondary malignancy than with other alkylating agents
Used for H/NHL

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antimetabolites

methotrexate

purine analogs (6-mercaptopurine, 6-thioguanine, fludarabine, cladribine)

pyrimidine analogs

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methotrexate

antimetabolite
Dihydrofolate reductase substrate and inhibitor
Tumor cells are more sensitive than normal cells = Greater accumulation in tumor cells
Blocks production of bases for DNA synth
Orally, IV, intrahtecally (doesn’t cross BBB)
Excreted in urine
May give high dose - followed by rescue with folinic acid (citrovorin, leucovorin)
AE
- Antifolate effects (bone marrow and GI problems)
- Chronic use can produce hepatotox - usually this is in patients taking it chronically for RA
Resistance - decrased drug accumulation, amplified DHFR, altered DHFR

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6-mercaptopurine, 6- thioguanine

pruine analogs
Oral
AE: Well tolerated - bone marrow depression at high doses
Blocks DNA and RNA synthesis - 6-MP inhibits AMP and GMP synthesis (stops the purine base synthesis), 6-TG incorperates into DNA or RNA and alters the function
Resistance from decrease in hprt activity or increase in alkaline phosphatase
- Hprt - enzyme in the purine salvage pathway - don’t need to make as much if you can salvage it

fludarabine

purine analog
Orally or IV as monophosphate
Dephosphorylated in plasma and absorbed by cells -> Once it gets into cells its phosphorylated just like any other nucleotide
Diphosphate inhibits ribonucleotide reductase
Triphosphate inhibits DNA poly and ligase, can also get incorporated into RNA/DNA and cause problems with replication
Effective as mono- or combiantion for CLL
AE: myelosuppresion, N/V

Cladribine (2-chlorodeoxyadensosine - 2-CDA)

adenosine look alike (anitmetabolite)
IV
Activated by deoxycytidine kinase (host enzyme that puts the first phosphate on it)
Triphosphate incorporated into DNA - causes strand breaks
Inhibits ribonucleotide reductase
Used for hairy cell leukemia, CLL and low grade lymphomas
Resistance if deoxycytidine kinase activity is absent, if ribonucleotide reductase is upregulated or by active efflux
AE: bone marrow suppression is dose limiting

pyrimidine analog

pyrimidine analog
IV or intrathecal
Activated by deoxycytidine kinase - polymorphic
Triphosphate incorporated into DNA, inhibts elongation and repair
Used for therapy of AML, also ALL
Far more toxic than purines: myelosuppresion, GI disturbances stomatitis

plant alkyloids

microtuble poisionsin (vinca)

topoisomerase inhibitors (etoposide (VP-16))

vinca alkaloids

Basics
- Biliary excretion
- IV admin
- Cuases metaphase arrest (CCS)
- Inhibit/reverses tubulin polymerization, disrupts mitotic spindles (microtubles)
- Isolated from vinca rosea (periwinkle)
- microtubule poisons
Drugs
- Vinblastine
  - AE: N/V, alopecia, bone marrow depression
- Vincristine
  - Structurally similar and mechanistically identical to vinblastine
  - Less toxic to bone marrow, no N/V
  - Use limited to short duration due to peripheral neuropathy - could be anything: numbness, pain, tingling in extremities

etoposide (VP-16)

Topo 2 inhibitor - double strand break (alows topo to break strands but not put back together), DNA degredation
Arrest cells in S-G2 stage (CCS)
Oral and IV
AE: N/V, alopecia, bone marrow suppression

anti tumor antibiotics

anthracyclines (doxorubicin, daunorubicin, idarubicin)

bleomycin

Basics
- Most produced by microbes (streptomyces)
- Interact with DNA and/or RNA, but most do not alkylate - it is a non covalent interaction
- These are still CCNS but they are more damaging if the cells are rapidly proliferating
- Block access to/function of DNA or RNA
- All given IV - these are large molecules and are not absorbed well
- Unique toxicities associated with these compounds

anthracyclines

Doxorubicin, daunorubicin, idarubicin
- Intercalate into DNA (slide inbetween the base pairs and cuase issues)
- Block topoisomerase 2, inhibit DNA and RNA syntehsis, cuase strand breaks (allow the topo to break the strands - but doesn’t let them put it back together)
- Generates free radicals
- IV - metabolized in liver
- AE: bone marrow suppresion, GI distress, severe alopecia
  - Signiture AE = cardiotoxicity
    - Function of cumulative dose
    - Idarubicin = less cardiotox
    - May be exacerbated by radiation or other drugs
      - You basically have to make a profile for the patient depending on: health status, age, other drugs - and then you can calculate a total lifetime dose that they can get without hurting the heart too bad
    - Arrhythmias, cardiomyopathy, CHF
      - These are selectively taken up in the mitochondria - have lots of this in heart muscle cells
    - Free radical mechanism
      - Minimize by administering dexrazoxane (this is not an anticancer drug - it binds iron and other things and prevents them from reacting with the reactive O2 species

bleomycin

* Mixture of glycopeptides * Binds DNA, generates radicals * Cuase strand breaks * Active in G2 (CCS) - we don’t know why its CCS it just is * AE * Hypersensitivity and cutaneous reactions can happen * Pulmonary toxicity = fibrosis (signature tox)

targeted therapies

hormones and hormone modulatiors biologicals (asparaginase, rituximab) singal transduction inhibitors (TK inhibtors - imatinib, dasatinib, ibrutinib, idealalisib) protosome inhibitors (bartezimib) differentiating agents (ATRA, arsenic trioxide, lenalidomide)

imatinib (gleevec)

* Inhibits Bcr-ABL and c-KIT tyrosine kinases * These are unique kinases that are only expressed in cancers with philadelphia chrom - hits the cancer without hitting other cells * Blocks growth factor signaling in CML * Used in any hematologic malignancy with philadelphia chrom * AE: myelosuppresive * Mild AE: edema and fluid retention, hepatotoxicity - many times these do not manifest

dasatinib, nilotinib

* Newer receptor tyrosine kinase inhbitors, broader spectrum * Useful when resistance to or poor tolerability to imatinib * The BCR-ABL gene can undergo mutation so that the protein produced wont bind to imatinib any more = resistance

ibrutinib

* Inhibits brutons tyrosine kinase (BTK) * Essential kinase for B cell receptor signaling * Oral * Metabolized by CYP3A4 - metabolite is 15X more potent as BTK inhibitor * High activity agasint mantle cell lymphoma, relapsed/refractory CLL (expecially with 17p deletion) * AE: GI, thrombocytopenia, neutropenia, infections, fatigue * More cells in the body use BTK than for BCR-ABL (which no cells except the cancer cells use) - so the AE are worse

idealalisib

* Oral PI3K inhbiotr * Metabolized by aldehyde oxidase and CYP3A4 (strong CYP3A inhibitor = slow substrate) * Active agaisnt relapsed CLL and SLL, relapsed follicular B cell NHL * AE: potentially fatal hepatotox, diarrhea/colitis, pneumonitis, intestinal perforation

borezimib

* Inhibits 26S proteosome * Disrupts multiple intracellular signaling cascades * Leads to apoptosis * IV * HL = 5.5 hr - HL of inhibiton = 24 hr (it stays in tissue for a while) * Used for mulitple myeloma, mantle cell lymphoma * AE: thrombocytopenia, fatigue, peripheral neuropathy - not in all patients * Hypotension upon infusion

all trans retinoic acid (ATRA)

* Used as mono therapy or with anthracycline or arsenic for APL * Binds to RAR-alpha receptor = promotes differentiation * Also promotes degradation of PML-RAR-a fusion protein, activates RAR-gamma * Resistance though enhanced clearance (CYP26A1 - not a CYP that we have heard about at this point in school) or loss of expression of fusion gene

arsenic trioxide (As2O3)

* Inhibits thioredoxin reductase - enhancing oxidative stress * Promotes modification and degradation of APL fusion protein * Cytotoxic and promotes differentiation

lenalidomide

* Thalidomide derivative * Used for CLL, mulitple myeloma * Lacks teratogenic, sedative effects of thalidomide * Thalidomide was used in UK as anti nausea meds for morning sickness - unfortunataly it was a teratogen and lots of babies were affected * May inhibit effects of rituximab - this drug downregulates the expression of CD20