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59 Cards in this Set
- Front
- Back
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Cell cycle
phases |
S
DNA synthesis 10 - 20 hrs G2 mitosis preparation 1 - 3 hrs M mitosis 1 hr G1 G0 normal resting varies varies |
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Gompertzian growth
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Tumor growth is exponential, but
Growth fraction is exponentially slowing |
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Log-cell Kill
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Cytotoxic agents kill by first-order kinetics
A single cell has the potential to kill the host (MULTIPLE ROUNDS NEEDED) |
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Drugs and Cell Cycle
classes of chemo agents |
Class 1 agent
Nonspecific cytotoxicity(all phases of cell cycle) Class 2 agent Proliferation dependent Phase specific Class 3 agent Proliferation dependent |
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Drug Resistance
Pleiotropic (multidrug) resistance mech |
Pleiotropic (multidrug) resistance is increasing
mdr I gene confers pleiotropic resistance and encodes a high-molecular-weight membrane protein called P-glycoprotein, ****an efflux pump***** |
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Pharmacokinetic Sanctuaries
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Appears as resistance
Cancer cells located in area not readily accessible by therapy (SAY cns) May be overcome using new administrative techniques |
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Shared Toxicities
OF CHEMO agents |
Bone marrow
Gastrointestinal Hair follicle Local Radiation recall Metabolic abnormalities Hepatic Renal Cardiac Pulmonary Nervous system Reproductive Carcinogenic ALL PREG D OR X |
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Rules of Combination Therapy
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All drugs must be active against tumor
Should act by different mechanisms Should have different dose-limiting toxicities Intermittent schedules should be used to permit recovery of normal cells Multiple cycles of therapy are needed, sometimes with drugs varied |
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Alkylating Agents
mOA |
the oldest agents
Introduce alkyl groups into nucleophiles through the formation of ***covalent**** bonds **Bifunctional alkylator**are more effective than monofunctional(has two arms with two guanines and makes it harder to repair the insertions) Class 1 agents******* |
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Alkylating Agents
named |
Mechlorethamine
Cyclophosphamide Ifosfamide Carmustine Lomustine Semustine Cisplatin Streptozocin |
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Mechlorethamine
class adv Rx |
an alkylator (the prototype)
Adverse reactions Myelosuppression Nausea and vomiting (use ondansetron and steroid_also helps with the inflam) Vesicant (blistering agent)(use special gloves) |
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Cyclophosphamide
class adv Rx |
converted by cyp450 to Phosphoramide mustard + **acrolein****** (both kill)
Myelosuppression Alopecia Cystitis **acrolein****** (hemorrhagic cystitis*** is possible)the dose limiting SE (HYDRATE) Drug interactions at biotransformation level are particularly important (esp inducers that increase conversion |
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Ifosfamide
class adv Rx |
Analogue of cyclophosphamide (alkyl)
Actions and effects are similar (BUT MORE POTENT) ****Cystitis risk is considerable Reduced by coadministration of thiol compound mesna (Mesnex) not usually nec w/cyclophos (it's very expensive) |
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Carmustine
Lomustine class adv Rx |
****Nitrosourea class***alkylator
Highly reactive same as other plus- Intermediate carbamylates proteins to inhibit DNA repair** Penetrates blood-brain-barrier Severe nausea and vomiting ******Myelosuppression*** ***Delayed and prolonged***LONG RECOVERY slow down round of chemo |
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Nitrosoureas
named |
Streptozocin (?)(beta cell guy)
Carmustine Lomustine (potent alkylator/repair -) big time myelosuppression delayed blah |
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Streptozocin
class adv Rx |
Nitrosourea compound with same mechanism of action and general toxicity (alkyl/repair (-) myelo huge)
Specifically toxic to beta-cells of the islets of Langerhans (insulomas) Primary indication for insulinomas Diabetogenic toxicity is inherent in mechanism |
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Temozolomide
Dacarbazine class adv Rx |
Biotransformed to methylhydrazine
Methylates guanine Mechanism of cytotoxicity Inhibits DNA repair mechanisms Temozolomide crosses blood brain barrier Adverse reactions Nausea and vomiting ****Delayed myelosuppression**** |
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Cisplatin
class moA |
Binds to DNA
Alters DNA structure Inhibits DNA synthesis Platinating (cross-linking) of adjacent guanines is **similar to alkylating action******(still x-link two guanines) (possible combo with alkyl) Class I agent |
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Cisplatin
adv Rxs |
the Platinating---alkloid...
*********Renal toxicity (the DLSE) Reduces with saline infusion and, sometimes, mannitol diuresis Hypomagnesemia and hypocalcemia may occur and be serious Correct hypocalcemia first Nausea and vomiting (used to be DLSE-now ondansetron and sedated sleep help) Hearing loss (due to e-lyte probs---says no loop diuretics with) |
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Antimetabolites
general moA |
Structurally related to naturally occurring compounds
Compete for binding sites on enzymes in critical pathways May become part of DNA or RNA |
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Antimetabolites
named |
Methotrexate
Fluorouracil Thioguanine Mercaptopurine Fludarabine Gemcitabine |
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Methotrexate
moA |
antimetabo
Competitive inhibitor of dihydrofolate reductase Enters cells by *****active-transport process**** S-phase Specific (inh DNA synt) Self Limiting (inh prot. synth) |
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Methotrexate Resistance
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Increased dihydrofolate reductase
Altered forms of dihydrofolate reductase Decreased methotrexate entry into cells*******(this is the one can get around-with Leucovorin rescue) |
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Leucovorin rescue?
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Methotrexate -a DHFR I
Reduced folate Uses same cellular transport system as methotrexate -the cancer cells have mutated MTX transporters and so we need to give a huge dose so enough gets in to kill the tumor- normal cells have ok transporters so even though the DHFR inhibitor is in the cell enough of the reduced stuff is around to funtion??????? they must be competing for a bunk transporter and the high dose DMX is winning |
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Methotrexate
adv RXs |
-Myelosuppression
-Nausea, vomiting and ulceration -***Renal toxicity High dose toxicity Due to drug precipitation in renal tubules (FLUSH) -Intrathecal administration Mild arachnoiditis Severe myelopathy or encephalopathy Requires ***prolonged leucovorin therapy***(CAN'T LEAVE BRAIN) **Pulmonary toxicity is allergic or hypersensitivity response More common among children, usually reversible **Powerful abortifacient and teratogen |
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Thioguanine 6-Mercaptopurine
moA |
ANTImetabolites
******Purine analogues Incorporated as thionucleotide into DNA and RNA - a faulty nucleotide Requires the enzyme hypoxanthine guanine-phosphoribosyltransferase ****(HGPRTase)******** Inhibition on purine nucleotide synthesis S-phase specific |
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Thioguanine 6-Mercaptopurine
p-kinetic blah |
Biotransformation elimination
******Mercaptopurine is inactivated by xanthine oxidase Can be inhibited by allopurinol Reduce dose to 25%*** of normal dose if given concurrent with ******allopurinol critical DIs (die if forget) |
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Thioguanine 6-Mercaptopurine
adverse rXs |
(purine analo)
Myelosuppression Hepatic toxicity |
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Fludarabine
moA adv rx |
Fluorinated purine analogue
Activated to 2-fluoroara-ATP Inhibits DNA synthesis Class I agent Adverse reactions Myelosuppression Neurotoxicity at higher doses |
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5-Fluorouracil
moA |
Halogenated pyrimidine analogue
Activated to form 5-fluoro-2’-deoxyuridine-5’-phosphate (FdUMP) Inhibits thymidylate synthetase to stop DNA synthesis **G1 and S phase specific** 5-fluorouridine triphosphate (5-fUTP) also is formed and incorporated into RNA Role of this “fraudulent RNA” is unclear (TRANSFORMED BY MULTIPLE PATHWAYS THUS R IS DIFFICULT) |
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5-Fluorouracil
Adverse reactions |
Schedule and ****route dependent*****
Oral mucositis, pharyngitis, diarrhea and alopecia most common after daily injections or continuous infusions Myelosuppression greatest after intravenous bolus infusion |
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Capecitabine
moA and all |
Oral prodrug of 5-fluorouracil
Pharmacology and toxicity essentially same as 5-fluorouracil |
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Cytarabine
moA and all |
Cytosine arabinoside is a pyrimidine antagonist
Requires phosphorylation to nucleotide form before incorporation into DNA synthesis pathway to interfere with DNA replication and function Adverse reactions are typical |
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Gemcitabine
moA and all |
Phosphorylated by kinases to nucleoside form that inhibits DNA synthesis
Parenteral administration, urinary excretion Adverse effects Nausea, vomiting,(BIG TIME) diarrhea ( Bone marrow depression |
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Antibiotics
in chemo |
Anthracyclines
Doxorubicin Daunorubicin Dactinomycin Bleomycin Etoposide Topotecan (from nat organisms thus cons abios) |
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Anthracyclines
named moA |
Doxorubicin
Daunorubicin Binds tightly to DNA Intercalates****** between base pairs Steric hindrance of DNA synthesis and DNA-dependent RNA synthesis Produces single-strand breaks in DNA Requires reaction with topoisomerase II *****Forms free radicals*******(thus big radiation recall) Mechanism of toxicity Binds to cell membranes to disrupt transport functions S-phase specific, though some cytotoxicity noted G2 phase |
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Doxorubicin
ADv RXs |
and Daunorubicin
*********Cardiac toxicity Free radical damage in the heart muscle May be reduced by concurrent administration of dexrazoxane, an iron chelator Early sign is 25% change in total QRS voltage ***********Lifetime cumulative risk******** ****550 mg/m2 ****450 mg/m2 for patients with radiation therapy to chest Myelosuppression Radiation recall Red urine |
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Dactinomycin
moA and all |
Intercalates with minor groove of DNA between guanine-cytosine
Interferes with DNA-dependent RNA polymerase Action on topoisomerase II or free radical generation may trigger single strand breaks Resistance largely by P-glycoprotein and DNA repair Adverse reactions similar to doxorubicin |
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Bleomycin
moA |
abio
Binds to DNA to form DNA-Bleomycin-Fe+2 complex intercalation of DNA base pairs single and double stranded breaks fragmentation of DNA ********Free radical (Bleomycin Fe+3 oxidation)***** strand breaks Slows cells in cell cycle phase G2 |
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Bleomycin
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Adverse reactions
***************Pulmonary 10% to 20% fatal****** Risk groups (Over 70 Prior radiation therapy Bleomycin cumulative dose > 400 units) Skin Hyperpigmentation Erythematous rashes Thickening of skin at pressure points Adverse reactions acute, fulminating anaphylactoid reaction patients with lymphoma after first or second dose |
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Etoposide
moA |
aBio
Complexes with topoisomerase II and DNA Single strand breaks in DNA G2 and S phase specific (only real spot where ss break can kill) Adverse reactions Relatively mild (but not that powerful of a drug) Myelosuppression |
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Antimitotics
named basic moA |
Vincristine
Vinblastine Paclitaxel Docetaxel Inhibit tubular processes, especially those related to mitotic spindle formation and function |
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Vincristine
Vinblastine moA |
ANTIMITotic
Bind to tubulin Interfere with mitotic spindle formation ****M-phase specific***** |
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Vincristine, Vinblastine
adv RXs |
myelosuppression
dose limiting for vinBLastine neurological toxicity dose limiting for viNCristine sensorimotor *peripheral **neuropathy decreased or absent Achilles’ and other tendon reflexes parerethises of fingers and toes generalized weakness and autonomic inactivity, esp. in elderly |
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Paclitaxel
Docetaxel moA |
pacli is taxol (antimitotics)
Binds to Beta-tubulin subunits and microtubulin filaments Prevents depolymerization Disrupts mitosis and many normal microtubular processes G2 and M phase specific |
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Paclitaxel
Docetaxel adv rxs |
Myelosuppression
esp Hx of other chemotherapies, radiation or liver disease (Common neutropenia pretreatment with granulocyte colony-stimulating factor) Neurotoxicity Cardiovascular side effects Hypotension and bradycardia Patients with existing cardiac problems should not be given these drugs PACLITAXEL******************Hypersensitivity, severe 1% - 2% with pretreatment of corticosteroids and antihistamines and an H2-blocker (acid blocker) 15% to 20% without above pretreatment |
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Steroids and Hormones
in chemo listed |
Prednisone
Tamoxifen Flutamide Goserelin Leuprolide |
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Prednisone
role here |
Triggers production of specific proteins that slow cellular growth and proliferation
(plus inh many cytokines stabalize membranes and help bigtime antiinfl) |
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Prednisone
typical SEs |
Immunosuppression
Adrenal suppression Ulcers and pancreatitis Hyperglycemia Glaucoma Osteoporosis Mood changes |
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Tamoxifen
moA adverse |
(SERM)
Competitively binds to estrogen receptors Little or no estrogen-agonist activity in breast, estrogen-agonist in other tissues Concentrates in estrogen target tissues Cancer should be estrogen-receptor positive (ER+) for greatest benefit also as prevention in older high risk Adverse reactions Hot flashes Vaginal dryness or discharge Mild nausea Exacerbation of bone pain and hypercalcemia in patients with bone metastases Monitor serum calcium in these patients |
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Goserelin
Leuprolide here |
(super) Agonists of luteinizing hormone-releasing hormone (LH-RH)
Chronic exposure abolishes gonadotropin release Takes 2 to 4 weeks of therapy Flutamide for initial stimulation of testosterone Hot flashes are most common adverse reaction |
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Flutamide
moA adv rx |
Nonsteroidal antiandrogen
Competes with testosterone Adverse reactions Hot flashes Loss of libido Impotence Nausea and diarrhea |
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Aromatase Inhibitors
named function adverse |
Aminoglutethimide
Anastrozole Letrozole Exemestane Interferes with conversion of cholesterol to pregnenolone Blocks virtually all steroid synthesis Adrenal insufficiency Less problem with Anastrozole, letrozole and exemestane Morbilliform rash (transient) |
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Monoclonal Antibodies
in chemo named |
Rituximab (binds b-lymphos)
Trastuzumab (her2) |
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Rituximab
moA adverse |
(a sensitizing agent-can senstize for further tx)
IGG1 kappa chimeric mouse/human antibody Binds to CD20 antigen on B-lymphocytes Depletes B-lymphocytes May sensitize lymphoma** cells to some cytotoxins Ab think hypersensi |
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Trastuzumab
moA |
(Herceptin)
Binds to oncogene HER2 Overexpressed in some breast cancers Inhibits growth of tumors that overexpress HER2****** Specific test is available to determine HER2 status |
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Monoclonal Antibodies
adv Rxs |
Hypersensitivity or allergic reactions
Chills fever asthenia Pain nausea vomiting Headache Cardiac toxicity Especially with other cardiotoxic drugs |
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Imatinib
moa |
(Gleevec)
Inhibitor of protein tyrosine kinase****** Inhibits proliferation and ********induces apoptosis****** Orally active, biotransformed Adverse effects Gastrointestinal upset Edema Bleeding Bone marrow depression |
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L-Asparaginase
moA adv rx |
Catalyzes deamination of asparagine to aspartic acid and ammonia
Effective *****only in tumor cells that require external asparagine***** for growth Hypersensitivity Decrease in clotting factors Pancreatitis Central neurological effects related to ammonia toxicity (lactulose**) |
