Alkylating Agents

! Drug Type Drug Name Cyclophosphamide Ifosamide MOA -DNA Alkylation; GC-->GT mispairing -Scission (depurination, imidazole ring opening) resulting in inter/intrastrand cross linking Therapeutic Uses -Cyclophosphamide: -NHL -CLL -AML -Breast, Ovarian -Ifosfamide: -Testicular -NHL -Cervical Carmustine Lomustine Nitrosureas DNA Alkylation, Mispairing, Scission Carmustine: -Brain -HD -Soft-tissue sarcoma -NSCLC MOR! Side Effects -Myelosuppression: Nadir of periph. Granulocytes w/in Not$mentioned$in$lecture$ 6-10 days; recovery 14-21 days. Hepatic Venooclusive Disease: Hepatic Clots -Hemorrhagic Cystitis: Tx: Mesna -Neurotoxicity: IfosfamideChloracetaldehyde; patient appears confused -Alopecia -Pulmonary fibrosis -Myelosuppression -Leukemogenic =Hepatic Venooclusive Disease -N/V -Pulmonary Fibrosis -Renal Failure -BMS -MAOI Weakening -Secondary Leukemia -Teratogen -Disulfirum Effect -BMS (thrombocytopenia, neutropenia) -HA -Fatigue Alkyl!Guanine!Transferase:!predominant! in!brain!cancer;!cleaves!adduct!from!DNA! allowing!for!continued!replication!

! Pharmacokinetics! Cyclophosphamide:!!CYP2B6! activated! Ifosamide:!CYP3A4!activated!

Nitrogen Mustards

-NHL -Melanoma

Not$mentioned$in$lecture$

Procarbazine Methylhydrazines

-DNA Methylation -Free Radical Production -DNARNAProtein Synthesis inhibited

-HD -NSCLC -Astrocytoma

GAlkyl!Guanine!Transferase!

Temozolomide Triazenes

BioactivationMTICDiazomethane -Methylates DNA on O(6) and N(7) of Guanine resulting in mispairing and scission

-Astrocytoma -Melanoma

GAlkyl!Guanine!Transferase!

Enzymatic!and!nonGenzymatic! activation! GTwo!different!Metabolites! 1)!!Methylhydrazine! 2)!Methyldiazene! ! G98%!Bioavailability! Greadily!penetrates!BBB!

Cisplatin Pt Coordination Complexes Dacarbazine Bulsulfan

-Forms DNA Adduct -Inhibits DNA replication and transcription -Breaks/miscoding at N(7) Guanine

-Testicular -Ovarian -Cervix -Bladder -N/SCLC -Dacarbazine: Soft-tissue Sarcomas, Brain -Bulsulfan: CML

-BMS -Peripheral Neuropathy -Ototoxicity -Hypersensitivity Rx (anaphylaxis) -Nephrotoxicity (Tx: Normal Saline hydration, diuresis, Amifostine (cytoprotective) -Myelosuppression -N/V -Leukemogenic (B) -Tumor Lysis Disease (B) -Extravasation (D) -Hyperuricemiarenal damage, Tx: Allopurinol

GLoss!of!MMR;!no!apoptosis!when!DNA! has!the!miscode!at!N(7)!Guanine!

Not$mentioned$in$lecture$

-DNA Alkylation, Mispairing, Scission

Alkyl Sulfonates (NOT on list, but within lecture)

Not$mentioned$in$lecture$

Not$mentioned$in$lecture$

Antimetabolites
! Drug Type Drug Name Methotrexate MOA S-Phase Specific Inhibition of Dihydrofolate Reductase (DHFR) -Inhib. DNA/RNA synthesis by elimination of methyl donor tetrahydrofolate in purine biosynthesis Therapeutic Uses -ALL -CNS Leukemia -GTN -Breast -NHL -5-FU: -Colorectal -Breast -Gastric -Capecitabine: -Breast -GI -Cytarabine: -AML -ALL -NHL -Gemcitabine: -Pancreatic -NSCLC -Breast -6-MP: -ALL -6-TG: -AML -Pentostatin: -Hairy Cell Leukemia Side Effects -Myelosuppression -Pneumonitis -Mucositis -Hepatoxicity -Nephrotoxicity -Teratogenesis -Meningismus MOR! GDHFR!gene!amplification!(lung!cancer)! GMRP! GPolyglutamate!formation!(keeps! compound!in!the!cell)! Not$mentioned$in$lecture$

! Pharmacokinetics! GPrimarily!excreted!in!kidney;! reduce!dose!in!renal! compromised!as!metabolite!is! nephrotoxic! GTx:!Leucovorin!reverse!effects!of! high!dose!(Rescue)! 858FU:!Tx!with!Leucovorin! increases!the!Thymidylate! synthase!inhibition;!allows!for!a! decrease!in!5GFU!dose!without! compromising!the!efficacy! ! !

Folate Antagonists

5-Fluorouracil Capecitabine Cytarabine Gemcitabine

-5-FU: S-Phase Specific 5-FU5-F-Deoxyuridine Monophosphate; suicide substrate for Thymidylate Synthase and subsequent inhib. Of DNA synthesis -Capecitabine: 5-FU prodrug

-Pancreatic -Esophageal -Colorectal -CNS -Leukemia -Head/Neck -Bladder

Pyrimidine Analogs

-Cytarabine: Inhibits DNA Pol -Gencitabine: Inhibits RNA Reductase (G+S Phase Specific)

-5-FU: -N/V/D -Myelosuppression -Alopecia -Hand & Foot Syndrome -Increases Warfarin sensitivity, decrease Warfarin dose accordingly -Cytarabine: -Myelosuppression -Seizures -Pneumonitis -Gemcitabine: -Myelosuppression -Asthenia -Pneumonitis

6-Mercaptopurine Thioguanine Pentostatin Purine Analogs

-6-MP: S-Phase Specific -Along with 6-TG: decrease DNA and RNA synthesis as 6 Thioguanine NTs by inducing cytotoxicity -Pentostatin: decrease in DNA methylation leading in DNA strand breakage

-6-MP (and 6-TG): -Myelosuppression (neutropenia) -Rash -N/V/D -Hepatotoxic -Pentostatin: -Myelosuppression -N/V/D

Not$mentioned$in$lecture!

G68MP!(and!6GTG):! GThiopurine!Methyl!Transferase! (TPMT)!and!Xanthine!Oxidase! take!away!from!production!of!6G Thioguanine!NTs!! GXanthine!Oxidase!is!inhibited!by! Allopurinol!and!could!shift! towards!6GThioguanine!NTs!too! much,!so!must!decrease! Allopurinol!dosage!

! !

Natural Products
Drug Type Vinca Alkaloids Paclitaxel Taxoids Doxorubicin Anthracycline Antibiotics -DNA intercalation resulting in ss/ds DNA breaks -Binds topoII/DNA complex and wont allow for supercoiling to be relaxed -Free radical production (increased with the fresence of Fe) Drug Name Vincristine MOA M-Phase specific -Block cells in mitosis by binding tubulin and inhibiting microtubule polymerization M-Phase specific -Binds tubulin; blocks microtubule disassembly Therapeutic Uses -HD -NHL -Brain -ALL -Ovarian -Breast -N/SCLC -H/N -Kaposi Sarcoma -AML -ALL -HD -Kaposi Sarcoma -Breast -Neuroblastoma (Adrenal Medulla) -Colorectal -N/SCLC -Ovarian -Cervical -Testicular -HD -NHL -H/N -Cervical -Caposi Sarcoma Side Effects -Fatal when injected IT -Alopecia -Myelosuppression -SIADH (ADH Dysfx) -Constipation -Neuropathy: peripheral and paresthesia -Myelosuppression -Peripheral neuropathy -Mucositis (ulcers) -Hypersensitivty (poor solubility) -BMS (dose limiting) -Alopecia -Extravastation -Stomatitis -Secondary AML -Cytotoxicity: arrhythmia, CHF (Tx: Dexrazoxane; cardioprotective Fe Chelator) -BMS (neutropenia) -Diarrhea -Mucositis -Pulmonary toxicity -Skin toxicity -Idiosynchratic Rx (Lymphoma, HTN, bronchospasm, BMS)

! MOR! GMDR! GMRP! GTubulin!mutations! GMDR! GTubulin!mutations!

! Pharmacokinetics! GCYP3A4! GDecrease!dose!75%!with!hepatic! dysfx! GCYP3A4! GDecrease!dose!50G75%!with! hepatic!dysfx! ! GDecrease!dose!50%!with!hepatic! dysfx!

GMDR! GIncrease!in!Glutathione!Peroxidase! GDecrease!Topo!II!activity! !

Ironotecan Camptothecin Analogs Bleomycin (A2, B2)

-S-Phase Specific -Bind Topo I/DNA cleavable complex -ss DNA break -G2 Specific -DNA scission with O2 + Fe free radical generation

GMDR! GTopo!I!mutation! GDecrease!in!CE! GIncrease!in!Hydrolase! GIncrease!Glutathione! GDecrease!uptake! GIncrease!DNA!repair! !

Not$mentioned$in$lecture$

Bleomycins

Hydrolase!metabolism! Gdecrease!dose!with!renal!dysfx!

Hormones
Drug Type Antiandrogens Anastrozole Aromatase Inhibitors Leuprolide GnRH Analogs Tamoxifen Antiestrogens -Aromatase Inhibition -CYP19 Inhibition -Decrease in Estradiols -Biphasic effect on pituitary 1) Stimulate FSH, LH initially 2) Long term densensitization along with a decrease in FSH, LH -Decrease testosterone (castration) and estrogen (postmenopausal) Estrogen Receptor antagonist -Decrease estrogen; estrogen stimulates TGF-B and IGF-1 which results in stimulation of tumor growth -Breast Drug Name Flutamide MOA Androgen receptor antagonist Therapeutic Uses -Prostate cancer (combo with leuprolide) Side Effects -Gynecomastia -Hot flashes -Decrease in libido -Hepatotoxic -Musculoskeletal pain -Fatigue -Headaches -Hot flashes -Transient flare -Pain at site of injection -Hot Flashes -Impotence -Gynecomastia -N/V -Hot flashes -Thromboembolic

! Pharmacokinetics! Not$mentioned$in$lecture$

MOR! Not$mentioned$in$lecture$

Not$mentioned$in$lecture$

Not$mentioned$in$lecture$

-Prostate

Not$mentioned$in$lecture$

Not$mentioned$in$lecture$ $

-Breast

Not$mentioned$in$lecture$

CYP2D6!substrate!

Immunomodulators
Drug Type Drug Name Aldesleukin MOA -Increase TNF-alpha, IL-1, IFN-Gamma -inhibits tumor growth Therapeutic Uses -Renal Cell Carcinoma (RCC) -Melanoma Side Effects -Capillary Leak Syndrome -Infx -BMS (RBC, platelets) -Change in mental status -Throid fx impairment -Arrhythmia

$ MOR$ Not$mentioned$in$lecture$

! Pharmacokinetics! Not$mentioned$in$lecture$

Immunomodulator

$ $ $ $

$ $ $ $

Monoclonal Antibodies
Drug Type Monoclonal Antibody Trastuzumab Monoclonal Antibody -Fab: Binds human epidermal growth factor 2 (HER2) -Stimulates Antibody-Dependent Cellular Cytotoxicity of tumor cells (ADCC) -Breast (25% are HER2 overexpressive) -Prostate -Pancreatic -Lung -Ovarian Drug Name Rituximab MOA -Fab: Binds CD20 on B-Lymphocytes -Fc: Stimulates immune system for cell lysis Therapeutic Uses -NHL -CLL Side Effects -Arrhythmias -Hypersensitivity Rxs (HTN, Bronchospasm, Angioedema) -Hepatitis B Infx -Tumor Lysis Syndrome -Cardiotoxicity (CHR, HER2 expressed in heart) -Hypersensitivity Rxs

$ MOR$ Not$mentioned$in$lecture$

$ Pharmacokinetics$ Not$mentioned$in$lecture$

Not$mentioned$in$lecture$

Not$mentioned$in$lecture$

Protein-Tyosine Kinase Inhibitor

Drug Type ProteinTyrosine Kinase Inhibitor Drug Name Imatinib MOA -Inhibits tyrosine kinase associated with Bcl-Abl translocation; decrease in constitutive proliferation and stimulates apoptosis Therapeutic Uses -CML (Ph +) -ALL (Ph +) -GIST Side Effects -Diarrhea -Edema (periorbital, pulmonary) -BMS -Hepatotoxicity

MOR! Not$mentioned$in$lecture$

Pharmacokinetics! 8CYP3A4!metabolism!

Enzymes
Drug Type Enzyme Drug Name L-Asparaginase MOA -Hydrolysis of AsnAsp + NH3 -Deprives cancer cells of Asn for protein synthesis resulting in apoptosis Therapeutic Uses -ALL Side Effects -Hypersensitivity -Bleeding -Hyperglycemia -Hepatotoxicity -BMS (rare)

$ MOR$ Not$mentioned$in$lecture$

! Pharmacokinetics! Not$mentioned$in$lecture$