(1) CYTOTOXIC DRUGS

DRUG MOA CLINICAL USE TOXICITY ANTIDOTE

ALKYLATING AGENTS

Mechlorethamine

Bifunctional alkylation “Nitrogen Mustard” MOPP regimen for

HODGKIN’S LYMPHOMA

Tissue necrosis

Cyclophosphamide

“Phosphoramide Mustard” Hemorrhagic cystitis

Ifosfamide

Monofunctional alkylation Sarcomas Hemorrhagic cystitis Mesna

Melphalan Prior to Bone Marrow transplantation

Chlorambucil Chronic B-cell lymphocytic leukemia and lymphoma

Immunosuppressive therapy (SLE/ Rheumatoid therapy)

Busulfan Prior to Bone Marrow transplantation

Venoocclusive disease of the liver

Nitrosoureas

Penetrates the CSF “Carmustine” / BCNU

Gliomas; Brain tumors Multiple myeloma Bone marrow transplant

Phenobarbital

Dacarbazine Generates active metabolite: MTIC (Monomethyl triazenoimidazole carboxamide)

ABVD regimen for HODGKIN’S LYMPHOMA

Flu-like syndrome of fever malaise, myalgias

Acetaminophen predication

Temozolomide

Dacarbazine analog Gliomas Radiation therapy

ANTIMETABOLITES

(1) FOLIC ACID ANALOGS

Methotrexate

Permetrexed

Inhibits DHFR enzyme (DIHYDROFOLATE REDUCTASE)

S-phase specific

Unable to polyglutamate methotrexate Multifolate antagonist Inhibits tumor enzymes

Intrathecal prophylaxis in

lymphomas & leukemias Choriocarcinoma

NON-HODGKIN’S

LYMPHOMA Osteosarcoma Leukemia Urine alkalinization

1

st line metastatic

mesethelioma 2

nd line metastatic non-

small cell lung cancer

Accumulation in 3rd

spaces (Ascites, Pleural effusion) Bone marrow suppression

Leucovorin Vitamin B and Folic acid

(2) PYRIMIDINE ANALOGS

5-FU

Capecitabine (prodrug of 5-FU)

Cytarabine

Inhibits Thymidilate Synthase Inactivated by Dihydropyrimidine Dehydrogenase enzyme in the liver Converted by Thymidine Phosphorylase to 5-FU Analog of 2-deoxycytidine Converted by Deoxycytidine kinase to an active for of 5-

Colorectal cancer Breast cancer

----

Induction of remission to

ALL

Hand-foot syndrome Myelosuppression GI disturbances Conjunctivitis

Leucovorin

Gemcitabine monophosphate nucleotide

----

Only drug effective for

pancreatic cancer Mild therapy; no alopecia

Myelosuppresion

(3) PURINE ANALOGS – inhibits HGPRT enzymes

Mercaptopurine Guanine analog Induction of remission to ALL Myelosuppression

Thioguanine

Guanine analog Induction of remission to AML

Myelosuppression

Fludarabine Adenosine analog Chronic lymphocytic leukemia

CD4 T-cells depletion

Cladribine Adenosine analog Hairy cell leukemia

CD4-Tcells depletion

ANTIMITOTIC

(1) VINCA ALKALOIDS –

Vincristine

M-phase specific; Binds to tubulin causing microtubule dissollution

NON-HODGKIN’S

LYMPHOMA together with CHOP (Cyclo, Prednisone, Doxorubicin)

HODKIN’S LYMPHOMA together with MOPP (Meclorethamine, Prednisone, Procarbazine)

Neurotoxicity, numbness, tingling, loss of DTR

Vinblastine

HODGKIN’S LYMPHOMA together with ABVD (Doxorubicin, dacarbazine, bleomycin)

Myelosuppression

Vinorelbine

Adjuvant and metastatic NSCLCA Myelosuppression

(2) TAXANE

Paclitaxel

Promotes, rather than inhibits microtubule formation Prevents microtubule destabilization

Breast cancer Lung cancer Ovarian cancer

Neutropenia Neuropathy

Cromophore vehicle

Docetaxel

More pronounced neutropenia than paclitaxel Metabolized in the liver by CYT p450

(3) EPOTHILONES

Ixabepilone Similar to taxanesbut MORE POTENT!

Metastatic Breast cancer

Metabolized in the liver by CYT p450

TOPOISOMERASE- INTERACTIVE AGENTS

(1) CAMPHOTERICIN

Irinotecan Major excretion pathway is GLUCORONIDATION by UGT1A1

s Patients with CRIGGLER NAJAR/ GILBERT’S SYNDROME are more affected Delayed & Acute diarrhea

TOPOTECAN

Metastatic ovarian cancer

Neutropenia

(2) EPIPODOPHYLLOTOXINS

Etoposide Conditions lowering albumin levels will lead to increased free fraction, increasing toxicities

Acute non-lymphocytic leukemia

TUMOR ANTIBIOTICS

(1) ANTHRACYCLINES

Doxorubicin Binds with Topoisomerase-II Generates free radicals Intercalates DNA Promotes apoptosis

Tumor antibiotic from

streptococcus spp.

Lymphomas, Leukemia, Breast cancer, Sarcoma, SCLCA

Cardiotoxicity due to free radicals generated

Daunorubicin ALL and AML

Epirubicin Breast Cancer Less cardiotoxic

Mitoxantrone Acute non-lymphocytic leukemia, hormone-resistant prostate cancer

Liposomal doxorubicin Ovarian cancer Lymphomas

Less cardiotoxic, less neutropenia

(2) BLEOMYCIN Oxidative DNA damage Pulmonary fibrosis

Decline in CO2 diffusion capacity

Cutaneous toxicity

(3) MITOMYCIN ANAL CANCER! HUS

PLATINUM COMPOUNDS – forms DNA ‘ADDUCTS’ which are recognized by MMR, that will promote apoptosis

Cisplatin Germ cell tumor Lung cancer Head and neck cancer Ovarian cancer

Nephrotoxicity Most emetogenic

Renal toxicity Ototoxicity Myelosuppression

Carboplatin Ovarian cancer Lung cancer

Less reactive than cisplatin, better tolerated

Oxaliplatin GI cancer, Ovarian cancer Germ cell cancer Cervical cancer Pancreatic cancer

Less neutropenia Less nephrotoxic, more neuropathic

L-asparaginase ALL Hypersenistivity reactions Mimimal Bone marrow and GI toxicity Hyperglycemia, Hypoalbuminemia, protein C and S deficiency

Mitotane Adrenocortical carcinoma

(2) HORMONAL TREATMENT DRUG MOA CLINICAL USE TOXICITY

Adrenocorticosteroids Promote apoptosis Immunosuppresion Glucose intolerance Osteoporosis Water retention GI ulcers

Aromatase Inhibitors Prevent formation of estrogen from adrenal gland and adipose tissue by inhibiting AROMATASE

Bone mineral density, bone pains, increased fracture rates Musculoskeletal problems!

For post-menopausal ER/PR+ breast cancer patients in adjuvant, neoadjuvant, metastatic setting

Anti-Estrogen Blocks estrogen receptors itself Thrombosis risk Endometrial CA Hot flashes, nausea, vomiting, menstrual irregularities

GnRH analogs Stimulates FSH and LH production by the pituitary gland then will late cause negative feedback inhibition

Breast cancer Prostate cancer

Initial flare reaction

Anti-androgen Binds to androgen receptors and causes complete androgen blockade

Prostate cancer Decreased libido Hot flashes Gynecomastia Mastodynia Paradoxical stimulation of androgen receptors

BIOLOGICAL RESPONSE MODIFIERS

DRUG CLINICAL USE SIDE EFFECT ANTIDOTE

Interleukin-2 Expands T-cell response that is cytolytic for tumor cells Melanoma Renal cell carcinoma AML

Hypotension Peripheral edema Azotemia

G-CSF Filgrastim/ Lenograstim Expands population of neutrophil precursors Prophylaxis for chemotherapy induced neutropenia

Fever Chills

TARGETED RESPONSE

DRUG CLINICAL USE SIDE EFFECT ANTIDOTE

MONOCLONAL ANTIBODIES

Traztuzimab Her2 receptor Breast cancer CHF Hypersensitivity

Bevacizumab Vegf receptor Angiogenesis Hypertension, bleeding, proteinuria Hypersensitivity reactions

Cetuximab EGFR receptor Colorectal cancer Head and neck cancer

Skin rashes Hypersensitivity reactions

Panitumomab EGFR receptor Colorectal cancer Hypersensitivity reactions

Rituximab CD20 receptor B-cell lymphomas Hypersensitivity reactions

TYROSINE KINASE INHIBITORS

Imatinib (Gleevec) Bcr-Abl TKO in CML CD 117 TKl in GIST

Rashes Asthenia Weakness

Gefitinib EGFR TKl in NSCLCA

Erlotinib EGFR TKl in NSCLCA

Sunitinib Multikinase Renal and liver cancer

Sorafenib Multikinase Renal and liver cancer

Lapatinib EGFR and HER2 TKl Breast Head and neck cancer

PROTEOSOME INHIBITOR

Bortezomib Degrades proteosomes that denatures IKb

MTOR INHIBITOR

Everolimus Pancreatic neuroendocrine tumors Advanced renal cell cancer

Temsirolimus Advanced renal cell cancer

Intrathecal Administration Methotrexate Cytotoxic agent (Antimetabolite)

Cytarabine Cytotoxic agent (Antimetabolite)

Can cross Blood Brain Barrier Nitrosoureas Cytotoxic agent (Alkylating agent)

Temoxolomide Cytotoxic agent (Alkylating agent)

Teniposide Topoisomerase interactive agent

Hydroxyurea