Chemo 1 Flashcards by Kyra Porter

naming conventions - traditional chemotherapy: -platin

*platinum alkylating agent
*examples: cisplatin, carboplatin, oxaliplatin
*notes:
-platins are a type of traditional cytotoxic chemo
-MOA: cross-link DNA (cell cycle non-specific)

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naming conventions - traditional chemotherapy: -rubicin

*anthracyclines
*examples: doxorubicin, daunorubicin
*MOA: generate free radicals; intercalate in DNA → breaks in DNA → decreased replication; inhibit topoisomerase II; G2/M phase specific
*important ADE: dilated cardiomyopathy

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naming conventions - traditional chemotherapy: -tecan

*MOA: topoisomerase I inhibitors
*examples: ironotecan, topotecan

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naming conventions - traditional chemotherapy: -mycin

*antitumor antibiotics
*MOA: induces free radical formation → breaks in DNA strands; G2/M phase specific
*example: bleomycin
*important ADE: pulmonary fibrosis

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naming conventions - targeted therapy: -mab

monoclonal antibodies; examples:
-rituximab
-bevacizumab
-trastuzamab

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naming conventions for chemo: -inib/ilib/isib

small molecule inhibitors; examples:
-imatinib
-dasatinib
-erlotinib

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cell cycle and chemo - why it matters

*traditional chemotherapy targets rapidly dividing cells
*a subset of the traditional chemo agents work specifically in one portion of the cell cycle:
-G2 = bleomycin
-M = taxanes, vinca alkyloids, eribulin
-S = cytarabine, fluorouracil, methotrexate
-S/G2 = topoisomerase 1/2 inhibitors
*some agents are cell-cycle independent:
-platinums, alkylating agents, targeted agent

*goal = target as many aberrant, rapidly-dividing cells as possible while avoiding cell cycle of normal, healthy cells

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how do monoclonal antibodies work in cancer therapy?

*all bind extracellular targets to neutralize them or to promote immune system recognition
*destroys cells through:
-direct tumor effects
-antibody-dependent cellular cytotoxicity
-complement-mediated lysis
-induce apoptosis

*newer molecules contain a conjugated toxin that is delivered to the site of activity by the monoclonal antibody

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tyrosine kinases for cancer therapy

*normally TK → phosphorylation of proteins resulting in proliferation, differentiation, and survival of cells
*mutation on TK → uncontrolled replication of cells
*activity tightly controlled in normal cells
*TK inhibitors can be beneficial in blocking reproduction of cancer cells

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traditional chemotherapy classes

nucleotide synthesis (folate antagonists, purine analogues, pyrimidine analogues)
DNA damage (alkylating agents, platinums, antitumor antibiotics, topoisomerase inhibitors)
cellular division - mitotic inhibitors

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methotrexate - drug class & MOA

*reduced folic acid analog (i.e. mimics folate to disrupt nucleotide synthesis)
*MOA:
1. taken up intracellularly by cancer & healthy cells
2. competitively inhibits DIHYDROFOLATE REDUCTASE → decreased tetrahydrofolate → decreased purine and thymidylate
3. lack of purines and thymidylate → DECREASED DNA SYNTHESIS

note - S phase specific antimetabolite

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methotrexate - common clinical uses

*osteosarcoma
*acute lymphocytic leukemia
*non-hodgkins and CNS lymphomas
*breast/bladder cancer
*non-oncologic uses: rheumatoid arthritis, ectopic pregnancy

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what is the rescue therapy for high dose methotrexate

LEUCOVORIN (folinic acid)

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leucovorin (folinic acid) - MOA

*leucovorin = folinic acid
*directly converted into tetrahydrofolate (does not require dihydrofolate reductase, the enzyme that is inhibited by methotrexate)
*allows resumption of DNA synthesis, even in the presence of methotrexate

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methotrexate toxicities

*NEPHROTOXICITY
*MYELOSUPPRESSION
*GI toxicity (mucositis)
*hepatotoxicity
*neurotoxicity
*dermatitis
*death [if not given leucovorin]

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methotrexate toxicity - risk factors

*pre-existing renal dysfunction
*urine pH < 7
*concomitant medications (eliminate these if possible)
*Down syndrome
*third space fluids: ascites, pleural effusions

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fluorouracil (5-FU) - indications

*treatment of SOLID tumors including breast, colorectal, and other GI tumors
*non-oncologic uses: actinic keratoses and noninvasive skin cancers

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fluorouracil (5-FU) - MOA

*fluorinated analog of uracil → metabolized to FdUMP → inhibits thymidylate synthetase → decreases DNA synthesis

note - S phase specific antimetabolite

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fluorouracil (5-FU) & leucovorin synergy

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provides higher levels of tumor kill activity (effects of 5-FU enhanced with addition of leucovorin)

fluorouracil (5-FU) - toxicities

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*myelosuppression (if given as a bolus)
*bloody diarrhea and hand-foot syndrome (if given as continuous infusion)
*mucositis (if given as continuous infusion)
*dermatologic
*ocular
*nausea & vomiting (MILD)

6-mercaptopurine (6-MP) & azathioprine - MOA

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*6-MP: purine analog; inhibits de novo purine synthesis
*azathioprine is converted to 6-MP, and thus has similar activities

6-mercaptopurine (6-MP) - clinical uses

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leukemias (pediatric)

6-mercaptopurine (6-MP) - toxicities

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*myelosuppression
*immunosuppression
*hepatotoxicity

hydroxyurea - MOA

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*inhibits ribonucleotide reductase → leads to decreased DNA synthesis

also increases HbF in sickle cell disease

hydroxyurea - indications

*used primarily for **myeloproliferative disorders** (CML blast crisis, polycythemia vera) *non-oncology indications: **sickle cell disease** (increases HbF)

hydroxyurea - toxicity

*severe myelosuppression

alkylating agents class - MOA (detailed)

1. one 2-chloroethyl side chain undergoes a 1st order intramolecular cyclization 2. result is the release of Cl- and formation of a highly reactive aziridinium ion 3. binds to DNA base pairs, resulting in inter- or intra-strand crosslinking 4. outcomes of alkylating agent treatment: -template being replicated is misread or mismatched during DNA synthesis -**crosslinking prevents DNA strands from unwinding** -single or double-strand breaks in DNA occur -DNA molecule ineffective *cell cycle non-specific

alkylating agents class - MOA (simple)

cross-links DNA

common alkylating agents

*recall - MOA: **cross-link DNA** 1. phosphoramide mustards: **-cyclophosphamide -ifosfamide** 2. platinums (**"platins"**): -cisplatin -carboplatin -oxalitplatin

alkylating agents class toxicities

*myelosuppression (prolonged/delayed myelosuppression nadir) ***hemorrhagic cystitis** *infertility *alopecia *nausea/vomiting *secondary leukemias

cyclophosphamide clinical uses

*breast cancer, leukemia, and lymphomas *bone marrow transplant *graft-versus-host disease *immunosuppression in non-malignant diseases: rheumatic disorders, lupus, & autoimmune nephritis note - **cyclophosphamide is an alkylating agent (cross-links DNA)**

ifosfamide clinical uses

*soft tissue/bone sarcomas *lymphomas recall: **ifosfamide is an alkylating agent (cross-links DNA)**

cyclophosphamide/ifosfamide metabolism

***require bioactivation by liver** *inactive metabolite: **acrolein** → NO TUMOR KILLING, just **causes toxicities** (ifosfamide generates more) *active metabolite: phosphoramide mustard -> causes the cytotoxities to the tumor

hemorrhagic cystitis - dose-limiting toxicity of alkylating agents

*caused by **accumulation of ACROLEIN (inactive metabolite of cyclophosphamide/ifosfamide) in the bladder wall** *hematuria, urinary frequency, & irritation ***prevent with vigorous hydration & MESNA** *treat with bladder irrigation, alum irrigation, and other therapies *heme test urine while on therapy

what is the prevention for hemorrhagic cystitis associated with use of cyclophosphamide/ifosfamide

MESNA indicated for ANY dose of ifosfamide, but only high doses with cyclophosphamide

MESNA

*uroprotectant containing sulfhydryl group - **binds to acrolein in the bladder to form a nontoxic compound** *not systemically absorbed, so does not interfere with cytotoxic activity *indicated in: -cyclophosphamide > 1g/m2/dose -ifosfamide ANY DOSE ***effective in PREVENTION of hemorrhagic cystitis (from cyclophosphamide / ifosfamide)** only

cyclophosphamide/ifosfamide - toxicites

***hemorrhagic cystitis** *delayed nausea & vomiting *syndrome of inappropriate anti-diuretic hormone *pulmonary *neurotoxicity *renal Fanconi syndrome (in peds)

cisplatin - notes

*renally cleared ***nephrotoxicity** (if poor renal function, do not use) *prevent with aggressive hydration *toxicities: nephrotoxicity, lots of nausea and vomiting, peripheral neuropathy, neurotoxicity, hypersensitivity

carboplatin - notes

*NOT concentrated in the renal tubules; more efficiently cleared *dosing based no area under the curve (AUC) *toxicities: neurotoxicity, vomiting, hypersensitivity

platinums - clinical uses

*breast cancer *lung cancer *testicular cancer *gyn/onc: cervical and ovarian cancer *colorectal cancer *bladder cancer *lymphoma

oxaliplatin

*toxicity = peripheral neuropathy, myelopsuppression, hypersensitivity

platinum toxicity: hypersensitivity

*IgE-mediated process *increased risk with increased number of doses (>6) *can be treatment-limiting *may be revealed using allergen skin testing procedures

antitumor antibiotics - MOA

induce free radical formation → DNA strand breakage

bleomycin - MOA, uses, toxicities

*drug class = antitumor antibiotic *MOA: **induces free radical formation → BREAKS IN DNA STRANDS** *uses: testicular cancer & Hodgkin lymphoma *toxicities: **PULMONARY toxicity (pulmonary fibrosis)**, N/V, skin hyperpigmentation

dactinomycin - MOA, uses, toxicities

*drug class = antitumor antibiotic *MOA: **intercalates into DNA, preventing RNA synthesis** *uses: Wilms tumor, Ewing sarcoma, rhabdomyosarcoma *toxicities: N/V, myelosuppression

mitomycin C - MOA, uses, toxicities

*MOA: DNA strand breakage *uses: GI tumors, intravesicularly in bladder cancer

leucovorin (folinic acid) - clinical indication

*REQUIRED for high dose methotrexate b/c high dose MTX is lethal unless rescue (leucovorin) is given

Chemo 1 Flashcards

(47 cards)