CANCER PHARMACOLOGY

HemeOnc Domain

CATEGORY: NAME Nitrogen Mustards Cyclophosphamide

TYPES

DISEASE

ALKYLATING AGENTS MECHANISM

AE

OTHER Mechloroethamine

C. CYCLE non-specific

RESISTANCE (CP pg. 326)

suppress immune system (I.e. total body irradiation)

cross-link DNA; impair hemorrhagic cystitis replication --> apoptosis (drink LOTS of water or MESNA) , cardiomyophathy, alopecia renal/pulmonary

acrolein(hepatic non-specific metabolite) is toxic in urine CAUTION: rheumatic and immunologic conditions carmustine, lomustine; Penetrate BBB (CNS Fx) non-specific

BCNU, CCNU

Nitrosureas

chlorambucil busulfan

melphalan

multiple myeloma (CP pg. 404)

marrow aplasia, hepatic, Dermatitis pulmonary fibrosis, marrow aplasia, hyperpigmentation marrow aplasia

non-specific

L-phenylalanine; not recommended for SCT candidates; full benefit takes several months

non-specific An issue with multiple myeloma tx

carboplatin

platinum deriv.

Intrastrand DNA linkage

cisplatin

platinum deriv. lymphoma

Intrastrand DNA linkage

thrombocytopenia, neurotoxicity and nephrotoxicity (less dose depends on GFR! than others) neurotoxicity, nephrotoxicity, severe nausea and vomiting, ototoxicity, SIADH (suddeninappropriate release of anti-diuretic hormone)

non-specific

1) decreased cisplatin accumulation; 2) metallothionein inactivation; 3) inactivation by glutathione activation; 4) enhanced Pt.DNA adduct repiar; 5) Pt.DNA damage tolerance pathways - cell death

oxaliplatin

colon cancer

Dysesthesia, Pharyngolaryngeal (1% to 2%) - feel can't breath, Peripheral neuropathy (56%) worse with cold

cyclosporin CATEGORY: NAME methotrexate

immune supp. Antimetabolites MECHANISM block THF synthesis by acting on DHFR

TYPES folic acid analog

DISEASE ALL, AML, NHL

AE mouth ulcers, gut toxicity, hepatoxicity, and bone marrow suppression; Accumulates in fluid

OTHER C. CYCLE RESISTANCE FH neededs as a cofactor in S-phase specific - 1)impaired thymidylate synthesis; self-limiting transport into cell; CAUTION: edema and renal 2) impaired failure - can accumulate polygluatmate doses formation 3) increased or altered DHFR; 4)decreased thymidylate synthase DI:Allopurinol (inhibits S-phase specific xanthine oxidase , lower self-limiting by %75 or else toxic) AUGMENTED by Folinic acid; thalamic acid stabilizes effect short half-life S-phase specific self-limiting S-phase specific

6-mercaptopurine

purine analog

inh. DNA synthesis; metabolized by xanthine oxidase colon cancer inh. DNA synthesis

jaundice

5-flurouracil

pyrimidine analog

mucositis, diarrhea, hand-and-foot syndrome CNS, esp. cerebellar toxicity; conjunctivitis

cytosine arabinoside pyrimidine (ara-C) analog folinic acid formyl THF

myelodysplastic syndromes

inh. DNA synthesis Decreases toxicity of methotrexate, increases toxicity of 5-FU

CATEGORY: NAME Paclitaxel (Taxol)

TYPES Plants

DISEASE

Vincristine Doxorubicin (Adriamycin) Bleomycin

Plants Antibiotic/ anthracycline Antibiotic

Natural products MECHANISM stops DISassembly of MT: inhibits DNA synthesis; inhibits BCL-2: promotes apoptosis stops assembly of MT and DNA replication DNA topoisomerase II inhibitor, keeps knots metal chelator, makes superoxide, degrade DNA deprive asparigine, low exogenous supply of protein synthesis

AE OTHER Infusion reactions, myelosuppression, neuropathy, and mucositis neuropathy: tingling in from periwinkle fingers and toes cardiotoxicity, hair loss pulmonary fibrosis "bleomycin lung", skin pigmentation hypersensitivity, low albumin and coagulation factors, pancreatitis active in non-cycling cells!

C. CYCLE RESISTANCE M-phase specific MDR (transport out of cell)

M-phase specific MDR (transport out of cell) non-specific MDR (transport out of cell) non-specific

L-asparaginase

enzyme

ALL

CATEGORY: NAME Corticosteroids

TYPES Prednisone, dexamethasone

DISEASE lymphomas; Acute GVHD

Hormones and Antagonist MECHANISM lymphoblast lysis; promotes apoptosis unknown

Medroxyprogesteron Megestrol

Uterine/Breast, occasionally prostrate

AE peptic ulcer, obesity, diabetes, osteoporosis, psychosis, hypertension MP: weight gain

OTHER

C. CYCLE

RESISTANCE

Tamoxifen

Anti-Estrogen

breast cancer

Aminoglutithimide Exemestane Anastozole Letrozole Flutamide

breast cancer breast cancer Aromatase Inh. breast cancer breast cancer Anti-Androgen Prostate

blocks estrogen binding to receptor, blocks stimulation of breast cancer cells inhibits aromatase, which blocks androgen conversion to estrogen (postmenopausal wom) androgen receptor antagonist

endometrial cancer; thromboembolism

maintains bone density

decreased bone density; hot flashes; thromboembolism fluid retention/edema, gynecomastia, impotence, CVD risk

ancient irreversible competitive competitive

CATEGORY: NAME Interferon (alpha)

TYPES

DISEASE

Other MECHANISM activate RNA-ase, NK activity

Trastuzumab (Herceptin)

Monoclonal antiB

AE flu-like symptoms, thrombocytopenia, leucopenia, wt. loss EGFR, induce endocytosis, cardiomyopathy recruit NK cells; Her2/neu, PTEN-lipid phosphotasedeficiency promotes effectiveness ; induction of B-cell immunosuppression apoptosis BCR-ABL; blocks ATP, myelosuppression, fluid inhibits phosphorylation of retention substrates, and inhibits signal transduction

OTHER

C. CYCLE

RESISTANCE

only pats. W/ Her2/neu overexpression benefit; 50% benefit from PTEN deficiency

Activation of IGF-IR

Rituximab(Tiruxan) Imatinib (Gleevec)

Monoclonal antiB B-lymphocytes TyrKinase Inh. CML (Ph t(9,22))

Gefitinib (Iressa) Dasanitib Bortezomib

TyrKinase Inh. TyrKinase Inh. Proteasome Inh.

EGFR active against Imatinib resist Multiple myeloma reversible inhibitor of proteasome, prevents proteolysis of ubiquitnated proteins: disrupts homeostasis --> apoptosis CML (Ph t(9,22)) Multiple myeloma myelosuppression

peripheral neuropathy (reversible in most cases), thrombocytopenia

Thalidomide

Immunomodulator

teratogenic

Lenalidomide, more "potent" and more myelosuppression, different toxicities

Bevacizumab Angiogenesis (Avastin) Inh. Biphosphonates (I.e. Palliative pamidronate, zoledronic acid)

colon cancer? Multiple myeloma; any lytic bone disease

VEGF osteonecrosis of jaw.; renal dysfunction; GI effects Calcium and vit. D recommended daily; CAUTION: pts. w/ renal failure; type of renal function varies btwn bisphophonates

/Urinary(Renal)

Clopidogrel Tranexamic acid

Antiplatelet chronic blood loss reduce hemorrhage in pts.; inhibits fibrinolytics

bleeding, neutropenia (rare)

all-trans retinoic acid vitamin (ATRA) arsenic Hydroxyurea

APML (t(15,17) AML) APML (t(15,17) AML) relapse sickle cell anemia, myeloproliferative

vit. A derivative, differentiatng agent induce diff. or apoptosis inh. Ribonucleotide reducatse

"atrasyndrome":neutrophi lia hyperleucocytosis, cardia pigmentation, nail dystrophy, skin ulceration; almost none? Goodman/Gilman, pg. 1435 S-phase specific

COMMON SIDE EFFECTS MECHANISMS OF RESISTANCE 1) Nausea and Vomiting 1) Altered membrane transport 2) Mucositis 2) Increase target enzyme 3) BM toxicity: pancytopenia 3) Alter target enzyme 4) Infertility 4) Decrease drug activation 5) Reversible Alopecia 5) increase drug degredation 6) Tissue necrosis if drugs extravated during 6) enhanced DNA repair OTHER SIDE EFFECTS 7) subcellular redistribution BM toxicity: leukopenia, infections 8) decrease target enzyme immunosuppression thrombocytopenia anemia GI tract intestinal or oral ulceration diarrhea Hair Follicles alopecia Gonads menstrual irregularities including Wounds impaired healing Fetus teratogenesis esp. during 1st trimester

OTHER DRUGS ON CONTENT OBJECTIVE Citrovorum factor (leucovorin) and combo w/ 5-flurouracil and w/ methotrexate

Relationship of HER2/neu and PTEN of Trastuzumab (herceptin) PAIN MANAGEMENT Acetaminophen Aspirin NSAID Ibuprofen NSAID Naproxen NSAID Fenoprofen NSAID Ketoprofen NSAID Ketorolac tromethamine NSAID Morphine Opioids Methadone Opioids Hydromorphone Opioids Codeine Opioids Fentanyl Opioids Oxycodone Opioids Amitripyline AntiDepress Desipramine AntiDepress Duloxetine AntiDepress Carbamazepine AntiConvuls Valproate AntiConvuls Gabapentin AntiConvuls Clonazepam AntiConvuls Dexamethasone Corticosteroids Prednisone Corticosteroids DRUGS TO AVOID IN CANCER PAIN Meperidine Pentazocine Butorphanol Nalbuphine Buprenorphine Naloxone Naltrexone

Radiation Therapy Hx of Radiation Oncology Role of radiation oncologist Emerging radiation tx modalities Goodman/Gilman, Ch. 52 pg. 1435

Figure and hydroxyurea

ADM/ELIM

/hepatic

/RENAL

ADM/ELIM

/xanthine oxidase metabolizes /hepatic (80%), 1520% urine

ADM/ELIM

ADM/ELIM

ADM/ELIM

al)

** Citrovorum factor (leucovorin) (folinic acid?)

combo w/ 5-flurouracil and w/ methotrexate

Relationship of HER2/neu and PTEN of Trastuzumab (herceptin) PAIN MANAGEMENT Acetaminophen Aspirin Ibuprofen Naproxen Fenoprofen Ketoprofen Ketorolac tromethamine Morphine Methadone Hydromorphone Codeine Fentanyl Oxycodone Amitripyline Desipramine Duloxetine Carbamazepine Valproate Gabapentin Clonazepam Dexamethasone Prednisone

NSAID NSAID NSAID NSAID NSAID NSAID Opioids Opioids Opioids Opioids Opioids Opioids AntiDepress AntiDepress AntiDepress AntiConvuls AntiConvuls AntiConvuls AntiConvuls Corticosteroids Corticosteroids

DRUGS TO AVOID IN CANCER PAIN Meperidine Pentazocine Butorphanol Nalbuphine Buprenorphine Naloxone Naltrexone

Radiation Therapy Hx of Radiation Oncology Role of radiation oncologist Emerging radiation tx modalities

Goodman/Gilman, Ch. 52 Figure and hydroxyurea pg. 1435