Drugs for leukemia and lymphomaPharmacologytanghuifang@zju.edu.cn2012-3-5

overview

Definition of Leukemia

Classification of Leukemia lymphocytic leukemia myelocytic leukemia

Type of Leukemia Acute: acute lymphocytic leukemiaALLacute myelocytic leukemiaAMLacute non-lymphocytic leukemiaANLL Chronic: chronic myelocytic leukemiaCMLchronic lymphocytic leukemiaCLL

Type of Acute Leukemia(ALL)Burkitt(ANLL)

5(70 40 )()

Lymphoma ():- Hodgkin lymphoma- Non-Hodgkin lymphoma

5040

Multiple myeloma harmartomaMMH B

60

Mechanisms of antineoplastic drugs Cytotoxic agents:Interrupt the biosynthesis of nucleic acidsInterrupt the structure and functions of DNAInterrupt transcription and synthesis of RNAInhibit the synthesis and functions of proteinsNon-cytotoxic agents:Regulate hormone levelsMolecular targeting agentsOthers

Classification of Cytotoxic agentsCell cycle specific agents CCSA) - generally most effective in hematologic malignancies and in solid tumors in which a relatively large proportion of the cells are proliferating or are in the growth fraction.Cell cycle non-specific agentsCCNSA) - particularly useful in low growth fraction solid tumors as well as in high growth fraction tumors

DNARNAMTX--ALL6-MP--ALL--HU--CMLDNA --Ara-C--AMLDNA HL NHLCTX--ALLMMHBusulfan--CMLBCNU--NHLMMC--CMLNHLBLM--CPT--AMLCML-- (Etoposid, VP-16)

RNADDACT--HLNHLADM--ALLAMLDRN--ALLAML ALL AMLCMLNHLL-L-ASP--ALL

glucocorticoids--ALL,CLL,HL,NHLPerdnisonepredinisoloneimatinib,--CML(FTase)--AMLBcl2ALLAML(rituximab,--B

C-KitFLT3c-KitBcr-AblP210PhCML 20 30Ph+CML

Drugs for ALLDrugs for remission induction () (Vincristine, VCR) (PrednisoneP) (Daunorubicin, DNR);(Adriamycin, ADM);L-(L-asparaginase, L-ASP); (Cyclophosphamide, CTX);(Cytarabine, Ara-C); (Methotrexate, MTX) Drugs for consolidation() L-(L-asparaginase, L-ASP) (Methotrexate, MTX) (Vincristine, VCR)(Cyclophosphamide, CTX);

Drugs for ALLDrugs for maintenance 6-MP (Methotrexate, MTX) (Vincristine, VCR) corticosteroidsDrugs for CNSL (Methotrexate, MTX) hydrocortisone,(Cytarabine, Ara-C);

Drugs for AMLDrugs for remission induction()(Daunorubicin, DNR(Cytarabine, Ara-C);Etoposide, VP16 M3APLAll trans retinoic acid, ATRA; As2O3 A(TanA)CD33: Gemtuzumab ozogamicin(GOMylotargCMA-676)GOWyethIsC_,4CD33()(calicheamicin)Drugs for consolidation (Cytarabine, Ara-C);(Daunorubicin, DNR6-MPMTX

New Drugs in AMLFLT3(DNA--1 Psc833IIITariquidarZosuquidarBC L2(Oblimersen)(Clofarabine)

Drugs for CML(Hydroxyurea, HU)(Busulfan, Bu)((homoharringtonine,HHT):CMLAra-C, 6-MP, CTXImatinib mesylate, IMIFN

Drugs for CLLCLLChlorambucil, CLBCLLFludarabine, Flu(2-):

Drugs for HL (ADM) Bleomycin, BLM (Vincristine, VCR)

(rituximab,:1997FDA CD20(Rituximab) NHLNHL20067NHLCTXADMVCRPVP16

Drugs for NHL

Methotrexate (MTX )Action mechanisms - cell cycle specific agent (s-phase) - inhibits dihydrofolate reductase (DHFR) - inhibits folic acid synthesis. Folic acid is needed for the de novo synthesis of the nucleoside thymidine dTMP, and purine base, required for DNA/RNA/protein synthesis

Methotrexate (MTX)Clinical uses - AL, including CNSL - chorionic epithelioma () - rheumatoid arthritis, psoriasis, induced abortion Drug interaction - NSAIDs - Penicillin

Methotrexate (MTX)Toxicity - Bone marrow suppression: leukopenia - Nausea and vomiting - Sores in the mouth or the lips (ulcerative stomatitis) - Hair loss (from head and body). - Signs of infection/fever, chills, cough, sore throat - Bruising or bleeding, black, tar-like stools. - Red spots on skin, rash, itchingLeucovorin ()

Methotrexate (MTX)Tolerance - decreased drug transport - decreased polyglutamate formation - synthesis of increased levels of DHFR through geneAmplification - altered DHFR with reduced affinity for methotrexate.

Cyclophosphamide (CTX)Action mechanisms - non cell cycle specific agent - alkylats guanine base of DNA Clinical uses: wild spectrum - Lymphoma - AL - Lung cancer - Breast cancer - Ovarian cancer - Nephrotic syndrome, rheumatiod arthritis

4-4-

Cyclophosphamide (CTX)Toxicity - Chemotherapy-induced nausea and vomiting (CINV) - Bone marrow suppression - Hair loss (alopecia ) - Hemorrhagic cystitis (Prevention: sodium 2-mercaptoethane sulfonate )

Adriamycin (ADM)Action mechanisms - non cell cycle specific agent - intercalates directed toward the minor groove. It has the highest preference for two adjacent G/C base pairs flanked on the 5' side by an A/T base pair, thereby interfering transcription process and mRNA synthesis. - inhibits the activity of topoisomerase type II, breaks the genomic DNA (Idamycin, )

Adriamycin (ADM)Clinical uses: wild spectrum, especially for drug-resistant tumors - AL and blastic phase of CML - Lymphoma - Lung cancer - Breast cancer - Ovarian cancer - Stomach cancer - Bladder cancer - Liver cancer Should be only be administered in a rapid intravenous infusion (due to its low bioavailability).

Adriamycin (ADM)Toxicity - Bone marrow suppression - Nausea and vomiting - Cardiotoxicity (Prevention: dexrazoxiane) - Hair loss - Darkening of the skin - Renal, hepatic and cardiac function should be monitored routinely.

Vincristine (VCR)Action mechanisms - cell cycle specific agent (m-phase and G1-phase) - binds to tubulin dimers, inhibiting assembly of microtubule structures (spindle), thereby arrests mitosis in metaphase. - also interrupts RNA polymerase and protein synthesis (G1-phase)

Vincristine (VCR)Clinical uses: - ALL (with prednisone) -Lymphoma (NHL, and less, HL) - Lung cancer - Nephroblastoma Toxicity: - Peripheral neuropathy - Bone marrow suppression - Nausea and vomiting - Hair loss Should be only be administered by intravenous injection (due to its low bioavailability).

Cytarabine (Ara-C)Action mechanisms - cell cycle specific agent (s-phase) - the derivative Ara-CTP inhibits DNA and RNA polymerase and nucleotide reductase enzymes needed for DNA synthesis, thereby interfering DNA chain elongation and repair. - Ara-CTP is incorporated directly into DNA and functions as a DNA terminator, interfering DNA chain elongation.

Cytarabine (Ara-C)Clinical uses: mainly for hematologic cancers - AML (M3/M4/M5) - Lymphoma - ALL - CNSLShould be only be given by continuous intravenous infusion due to its fast inactivation.

Cytarabine (Ara-C)Toxicity: - Bone marrow suppression (leukopenia, thrombocytopenia, anemia, megaloblastosis) - Anorexia (cerebellar toxicity), nausea, vomiting - Hepatic dysfunction - stomatitis (), conjunctivitis (), pneumonitis (), fever, and dermatitis ().

Mercaptopurine (6-MP)Action mechanisms - cell cycle specific agent (in particular s-phase and also postpones G1-phase) - the derivative TIMP inhibits purine nucleotide synthesis and metabolism.

Clinical uses: - ALL (for maintenance therapy, due to its slow action) - Pediatric NHL - polycythemia vera () - inflammatory bowel diseaseToxicity - myelosuppression - diarrhea, nausea, vomiting, loss of appetite, stomach/abdominal pain - mouth sores - bleeding - Allopurinol increases the toxicity of 6-MP. Mercaptopurine (6-MP)