Anti-Neoplastics

Antimetabolites◦Methotrexate◦5-FU◦Mercaptopurine◦Azathioprine

Alkylating Agents◦Cyclophosphamide◦Cisplatin◦Chlorambucil◦Carmustine

Cytotoxic Antibiotics◦Doxorubicin◦Dactinomycin◦Daunorubicin◦Bleomycin

Natural Products◦Vincristine◦Vinblastine◦Etoposide◦Paclitaxel

Hormones◦Tamoxifen◦Anastrazole◦Prednisone

Monoclonal Ab◦Trastuzumab◦Rituximab

Immunosuppressants◦Azathioprine◦Prednisolone◦Cyclosporine

Others◦Asparaginase◦Imatinib Mesylate◦Hydroxyurea

Drugs acting at Cell Cycle phases

S phase◦Methotrexate blocks dihydrofolate reductase◦5 – FU inhibits thymidylate synthase◦Mercaptopurine inhibits purine nucleotide

interconversions◦Hydroxyurea inhibits ribonucleotide reductase◦Pentostatin inhibits adenosine deaminase

Drugs acting at Cell Cycle phases

G2 phase◦ Bleomycin fragments DNA

M phase◦ Vincristine & Vinblastine binds tubulin & blocks MT

polymerization◦ Paclitaxel prevents MT depolymerization; promotes

polymerizationG1 phase

◦ Dactinomycin binds DNA & inhibits DNA-dependent RNA synthesis

Between S and G2◦ Etoposide interferes with topo II◦ Dactinomycin

What is an induction regime?

High dose of tx for a short period of time to reduce burden on cells

CCNS – Cell cycle nonspecific drugs

Used for cancers with low percentage of mitotic cells

Cyclophosphamide, busulphan, chlorambucil

Doxorubicin, daunorubicin, dactinomycinCisplatinRecruitment: initial use of CCNS drugs

achieves a significant log kill which causes more cells in Go to go into G1; then CCS drugs are given

Log – Kill concept

Drug/irradiation kills a constant proportion of cells in population, not fixed number of cancer cells

One log kill = 90% decrease in cell pop3 log kill = 99.9% decreaseSmaller tumor will have greater portion of

cells killed than larger tumor but they regrow quicker between cycles of therapy

Breast Cancer Combo

CyclophosphamideMethotrexate5-FU

Pancreatic Cancer Combo

DoxorubicinMethotrexate5-FU

Ovarian Cancer Combo

CisplatinPaclitaxel

Testicular Cancer Combo

CisplatinVinblastineBleomycin

Non Hodgkin’s Lymphoma Combo

CyclophosphamideDoxorubicinVincristinePrednisoneRituximab

Hodgkin’s Disease Combo

MechlorethamineVincristinePrednisoneProcarbazine

DoxorubicinBleomycinVinblastineDacarbazine

Drugs w/ features you must know

CytarabineCapecitabineCarmustineEtoposideTopotecanFulvestrantFlutamide &

FinasterideLeuprolide

RituximabHydroxyureaImatinib Mesylate

Cytarabine

AntimetaboliteDOC for AMLMoA: blocks DNA strand elongationNeurotoxic

Etoposide

Stabilizes the topo II – DNA complex causing dsDNA breaks during DNA replication

Dose limiting leukopeniaTreat first time and metastatic testicular

cancermay cause AML!!

Capecitabine

Oral prodrug converted to 5-FUMoA: inhibits thymidylate synthaseUseful for paclitaxel and doxorubicin –

resistant pts with colorectal or metastatic breast cancers

Carmustine

Alkylating agent; nitrosoureasMost alkylating agents taken up by active

transport but nitrosoureas taken up by passive transport

Liphopilic & passes BBB CNS ToxicityUsed for CNS cancers that are metastatic

malignant astrocytoma

Topotecan

Unique topo I inhibitor, preventing religation of bits of helices accumulation of single stranded breaks in DNA

Dose limiting neutropenia

Fulvestrant

Antiestrogen for hormone-sensitive tumors

Give to post-menopausal women who are resistant to tamoxifen

Flutamide & Finestiride

Flutamide is a nonsteroidal androgen antagonist which inhibits the translocation of steroid receptors to the nucleus

Finasteride is a 5-alpha reductase inhibitor which inhibits synthesis of dihydrotestosterone

Both used to treat prostate cancer

Leuprolide

GnRH analog which acts as a partial agonist at GnRH receptors

When administered in constant doses to maintain stable blood levels, it inhibits the release of LH and FSH

Used in tx of prostate cancer

Rituximab

This is an unconjugated chimeric (murine/human) antiCD20 monoclonal antibody which binds to the CD20 antigen on follicular B cells in Non Hodgkins lymphoma

Hydroxyurea

Inhibits ribonucleotide reductase ribonucleotides to deoxyribonucleotides

Used for myeloproliferative disorders

Imatinib Mesylate

Inhibits bcr-abl tyrosine kinase found in chronic myelocytic leukemia (CML)

Antimetabolites

Methotrexate (CCS works during S phase)

Uses◦Solid tumors such as choriocarcinoma◦Osteogenic sarcoma◦Acute Lymphoblastic Leukemia (ALL)◦Psoriasis◦Abortifacient

Looks like folate take up by cells readily

MoA of Methotrexate

Inhibits dihydrofolate ReductaseThis enzyme reduces folate to

tetrahydrofolate which is a one carbon unit carrier used in synthesis of purines and pyrimidines which are part of DNA and RNA cell replication

ANTIDOTE: Leucovorin folinic acid rescue◦Host cells are rescued while cancer cells die

Methotrexate Toxicity

NephrotoxicityMyelosuppression

◦Neutropenia, thrombocytopenia, mucositis, diarrhea, and GI ulceration (oral)

◦G-CSF can counteract leukopeniaPulmonary toxicity and hepatotoxicity

(long term)

Other Antimetabolites

Pyrimidine analogs◦5 – FU◦Capecitabine 5-FU◦Cytarabine

5 – FU◦MoA: inihibit thymidylate synthase◦Uses: colon, breast, rectal, gastric, pancreatic

cancer◦Capecitabine is same but one of the newest

drugs for pancreatic cancer

Toxicity of 5-FU and Antimetabolites

Anorexia, nauseaAlopeciaStomatitis and diarrheaMyelosuppression (less for capecitaine)Maculopapular rash

Resistance develops when thymidylate synthase becomes less sensitive to the drug

Purine Analogs

Azathioprine, MercaptopurineMoA: as nucleotides they inhibit

phosphoribosylpyrophosphate (PRPP) synthetase reduction in PRPP

They also inhibit PRPP amidotransferase reduction in phosphoribosylamine

Block de novo PURINE synthesis and salvage pathways

Toxicity:◦ Bone marrow suppression◦ Leukopenia◦ Hyperuricemia (Mercaptopurine)◦ Hepatotoxicity

Purine analogs

Pentostatin◦Uses: Hairy Cell Leukemia◦MoA: blocks adenosine deaminase

impairment of DNA replication and cell division◦Toxicity: Myelosuppression

Alkylating Agents

Cyclophosphamide (ifosphamide also)BusulphanCarmustine (nitrosoureas)

Cyclophosphamide

MoA: prodrug converted in liver to active nitrogen mustard (nephrotoxic) and acrolein (causes cystitis) interferes with transcription and translation and causes increased ADH secretion (water reabsorption leading to hyponatremia results)◦Drug is given with high water load

ANTIDOTE: MesnaADH antidote: Demeclocycline

Cyclophosphamide Use and Toxicity

Uses◦Hodgkin’s disease◦Lymphomas, myeloma◦Leukemia◦Ovarian & breast tumors

Toxicity◦Myelosuppression◦Permanent amenorrhea and azoospermia◦Renal and bladder toxicity (hemorrhagic cystitis &

hematuria)◦Alopecia◦Cardiotoxic at high doses

Busulphan

MoA: cross-links DNA strands by covalently bonding guanine residues prevents DNA replication & transcription

Use: CMLToxicity:

◦Busulphan Lung - pulmonary fibrosis◦Busulphan tan – hyper pigmentation

Temozolamide

Some success in treating malignant gliomas (multiforme glioblastoma thought to be incurable)

Cytotoxic Antibiotics

DoxorubicinDaunorubicinDactinomycinBleomycin

All CCNS mostly

Doxorubicin

MoA: ◦Intercalates DNA and is topo II block/poison◦Increases radicals◦Causes extravasation ulcers and

inflammationUSES:

◦Breast, ovarian, bladder tumors – Solid tumors◦Bronchogenic carcinoma◦Lymphoma and leukemia

Doxorubicin Toxicity

CardiomyopathyColors urine redStomatitisAlopeciaAnemia, leukemia

ANTIDOTE for radicals: Dimethyl SulphoxideANTIDOTE for cardiomyopathy: Dexrazoxane

Daunorubicin

Similar to doxorubicinUse: LEUKEMIA

Dactinomycin

MoA: binds DNA Helix prevents transcription of DNA by RNA polymerase

USES◦Rhabdomyosarcoma◦Wilm’s tumor in children◦Ewing’s Tumor◦Kaposi’s sarcoma

Toxicity: Pancytopenia

Bleomycin

MoA: fragments DNA via free radicals cells accumulate in G2 phase

USES◦Lymphomas◦SCC◦Testicular carcinoma◦Choriocarcinoma

Toxicity: Pulmonary Fibrosis, hyperpigmentation

Natural Products

Vinca alkaloids: Vincristine and VinblastineEpidophyllotoxins: EtoposideCamptothecins: TopotecanTaxanes: Paclitaxel

Vinca Alkaloids

MoA: bind tubulin and prevent MT assembly; act in M phase

Vincristine (Neurotoxic—peripheral neuropathy, loss of deep tendon reflexes)◦Use: Hodgkin’s disease, rhabdomyosarcoma,

lymphomas, leukemia, neuroblastomaVinblastine (reversibly myelotoxic)

◦Use: Hodgkin’s, testicular carcinomaResistance assoc/ MDR gene mutation

Epidophyllotoxins - ETOPOSIDE

MoA: stabilizes topo II-DNA complex dsDNA breaks

Specific for late S and early G2 phasesUses: testicular carcinoma (less toxic than

other natural products), Hodgkin’s diseaseToxicity:

◦Leukopenia; hepatic and renal toxicity at high dose

◦May cause AML!!!

Taxane - Paclitaxel

MoA: inhibit MT disassembly abnormal/dysfunctional spindles

Uses◦Advanced ovarian cancer w/ cisplatin◦Metastatic ovarian or breast cancer

Toxicity◦Hypersensitivity reactions◦Neutropenia◦Peripheral neuropathy & muscle pain

Hormonal Chemotherapy

EstrogensAntiestrogens

◦Tamoxifen◦Fulvestrant◦Anastrazole

AndrogensAntiandrogens

◦Flutamide◦Finasteride

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