Chemo 1 Flashcards
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)
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
naming conventions - traditional chemotherapy: -tecan
*MOA: topoisomerase I inhibitors
*examples: ironotecan, topotecan
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
naming conventions - targeted therapy: -mab
monoclonal antibodies; examples:
-rituximab
-bevacizumab
-trastuzamab
naming conventions for chemo: -inib/ilib/isib
small molecule inhibitors; examples:
-imatinib
-dasatinib
-erlotinib
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
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
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
traditional chemotherapy classes
- nucleotide synthesis (folate antagonists, purine analogues, pyrimidine analogues)
- DNA damage (alkylating agents, platinums, antitumor antibiotics, topoisomerase inhibitors)
- cellular division - mitotic inhibitors
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
methotrexate - common clinical uses
*osteosarcoma
*acute lymphocytic leukemia
*non-hodgkins and CNS lymphomas
*breast/bladder cancer
*non-oncologic uses: rheumatoid arthritis, ectopic pregnancy
what is the rescue therapy for high dose methotrexate
LEUCOVORIN (folinic acid)
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
methotrexate toxicities
*NEPHROTOXICITY
*MYELOSUPPRESSION
*GI toxicity (mucositis)
*hepatotoxicity
*neurotoxicity
*dermatitis
*death [if not given leucovorin]
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
fluorouracil (5-FU) - indications
*treatment of SOLID tumors including breast, colorectal, and other GI tumors
*non-oncologic uses: actinic keratoses and noninvasive skin cancers
fluorouracil (5-FU) - MOA
*fluorinated analog of uracil → metabolized to FdUMP → inhibits thymidylate synthetase → decreases DNA synthesis
note - S phase specific antimetabolite
fluorouracil (5-FU) & leucovorin synergy
provides higher levels of tumor kill activity (effects of 5-FU enhanced with addition of leucovorin)
fluorouracil (5-FU) - toxicities
*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
*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
leukemias (pediatric)
6-mercaptopurine (6-MP) - toxicities
*myelosuppression
*immunosuppression
*hepatotoxicity
hydroxyurea - MOA
*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)
- one 2-chloroethyl side chain undergoes a 1st order intramolecular cyclization
- result is the release of Cl- and formation of a highly reactive aziridinium ion
- binds to DNA base pairs, resulting in inter- or intra-strand crosslinking
- 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
