Anti-Neoplastics

• form intermediaries that bind to DNA causing intercalation causing cell death
• non cycle specific
• ex: cyclophosphamidem melphan, temozolomide, bendamustine

• Alkylating agent, used in lymphomas R-CHOP combo
• metabolized in liver into Acrolein, causes hemorrhagic cystitis
• prolonged use causes bladder cancer
• similar to ifosfamide

Alkylating agent, used in multiple myeloma, high dose chemo, stem cell transplants

Alkylating agent, spontaneous activation, oral, primary brain tumors, crosses BBB

Similar to alkylating agents and purine analogs, active in indolent lymphomas, follicular lymphoma

• Cisplatin, Carboplatin, Oxaliplatin
• similar function to alkylating: + charged cause DNA intercalation and non cell cycle death
• renal toxic, peripheral sensory neuropathies, ototoxic, highly emetogenic
• Used in Germ cell, colon, lung cancers

• Cause DNA damage via misincorporation, effective in S phase only: cycle specific
• Effective in continuous infusions, not leukemogenic
• Anti-folates, fluoropyrimidines, thiopurines, purine analogs, cytarabine, gemcitabine

• Must be polyglutamated before entering cell
• Inhibits DHFR depleting folate, blocking synthesis of thymidylate & purine nucleotides
• S phase only, ALL, Burkitt's lymphoma, RA
• Side effects: mucositis, nephrotoxic (crystalizes in urine), neurotoxic
• Give Leucovorin to spare some cells (bone marrow) 48 hours after methotrexate

• Similar to methotraxate, targets multiple enzymes: TS, DHFR
• S phase only, can also target solid tumors (lung cancer, mesothelioma)
• Give B12/folate to avoid toxicity

• GI, breast, cancers
• Enzymatically becomes 5'FdUMP inhibiting TS by incorporating into DNA interfering with synth/repair
• Can also enter RNA
• Leucovorin used: enhances stability of 5-FU-Folate-TS combo, doesn't rescue healthy cells
• Causes Diarrhea, hand-foot syndrome, if DPD deficient (5%) causes severe BM, neuro, GI toxicity

• Oral, 3 enzymatic rxns:
• liver makes it carboxylesterase, tumor cells have thymidine phosphorylase to make 5-FU
• same effects and side effects: D, N, V, hand-foot syndrome, myelosuppression
• colorectal/breast cancers

• Anti-metabolite, used in AML, ALL, NHL
• 50% cure rate in combinatio with anti-cycline
• N, D, stomatitis
• chemical conjunctivitis cerebellar ataxia at high levels

• Anti-metabolites, peds leukemia, adult ALL
• inhibition of purine synth, misincorp in DNA
• causes myelosuppression, mucositis, liver dysfunc
• 6-Mercaptopurine, 6-Thioguanine
• Require activation

• Purine analog, same mechanism, increases apoptosis
• CLL, indolent non-Hodgkin, non-cell cycle
• Synergistic with immunotherapy
• Myelosuppression, immunosuppression: opportunistic, fungal, viral, PCP

Anti-metabolite, 1 infusion cures hairy cell leukemia

• Analog of urea, inhibits DNA synth by inhibiting ribonucleotide reducatse
• S phase only, chronic myeloproliferative: CML, P Vera, essential thrombocytosis, sickle cell

• Vincritine (R-CHOP), vinblastine, vinorelbine
• Binds to tubulin, prevent polymerization of tubulin dimers, inhibit microtubule formation
• Arrests cell in M phase
• peripheral sensory neuropathy, at high doses, autonomic as well
• Breast, Lung, NHL, HD, Kaposi's

• similar to vinca alkaloids, stabilizes microtubules, prevents spindle formation, cell dies in M phase
• Paclitaxel, Doceaxel: breast lung, ovarian, prostate, bladder
• neuropathy seen
• hypersensitivity to cremaphore (deliverant)

• Topoisomerase inhibitors: AML, breast (curative)
• prevents DNA unwinding for replication/transcription
• Causes strand breaks, w/ Fe: free radical formation
• Myelosuppressive, vesicants (causes skin damage)
• dose dependent cardiotoxicity, causes 2ndary leukemias

• Topo-I inhibitors, causes DNA damage
• Irinotecan, topotecan
• Diarrhea, immnosuppression
• Colon, lung, ovarian, gastric cancers

• Etoposide: topo-II inhibitors, direct binding
• G phase: Germ cell, hodgkin/non-H lymph
• cause acute leukemia 2-3 yrs later (11q23 abnormality)

• Peptide binds to DNA and Fe: chromosomal abberations
• Hodg lymph and testicular: curative
• pulmonary toxicity: respiratory failure

Hydrolyzes asparagine to aspartic acid + NH₃ tumor cells can't replace aparagine and die: ALL only

• Most common form of ADT: causes short surge of testosterone then levels bottom out in 3-4 weeks
• Leuprolide and Gosrelin used
• can also be surgically castrated

• Competitively inhibit ligand of androgen receptor and act on cell surface
• Nilutamide, flutamide, biclutamide
• well tolerated, cause gynecomastia, vasomotor flushing, mastodynia, decreased libido
• Flutamide: diarrhea, nausea, reversible liver abnorm
• Nilutamide: visual issues, alcohol intolerance, allergic pneumonitis

• Selective estrogen receptor modulator
• most convertedto desmethylTAM, CYP2D6 converts it to endoxifen (active form)
• CYP2D6 defeciencies have less benefit
• TAM blocks estrogen stimulation of the breasts, inhibiting transcription/nuclear binding
• 1: treat metastatic breast cancer (remission, won't cure)
• 2: adjuvant treatment post surg/rad
• 3: prevent breast cancer in high risk women
• proestrogenic in bone/endometrium lining

• elimates estrogen production: post-menopause or oophorectomy only
• arthralgia, myalgia, bone loss

• CD20 antibody: lymphoid cells
• kills lymphoma cells in B cell lymphoma and CLL
• synergistic wtih chemo (R in R-CHOP)

• targets her2/neu in 30% of breast cancers, cause cell death
• her2 has to dimmerize, trastuzumab prevents dimerization/signal transduction
• metastatic/early breast cancer, only with her2/neu overexpression
• can cause heart failure, lowers L vent ejec frac

• Cetuximab or panitumumab
• target epidermal growth factor, prevents dimerization/signal transduction
• squamous cell cancers of head neck colon and lung
• acneiform rash: marker for response

• Gemtuzumab ozogamicin
• CD33 MAB linked to calicheamicin
• targets CD33+ cells and delivers drug there
• lysosome separates drug from antibody activating it
• infusion related toxicities, BM suppression, hepatotoxic

• Tyrosine kinase inhibitor
• used for CML: BCR-ABL fusion creates activated TK, imantinib blocks ATP binding site
• CML and GI stromal tumor, chronic myelomonoclonal leukemia
• causes neutropenia, edema
• 2nd gen: dasatinib nilotinib: more effective

TK inhibitor, targets EGFR TK, used in lung cancer

• inhibit Raf Kinase, VEGF receptor kinase inhibitor
• used in kidney and liver cancer

• Anaplastic lymphoma kinase
• lung cancers can respond to crizotinib: inactivating it
• causes short remessions

• unknown mechanism, used in multiple myeloma, myelodysplastic syndrome
• causes remission
• side effects: neuropathy, thromboembolism, sedation
• TERATOGENIC

• bortezomib: proteasome inhibitors
• remove ubiquinated proteins
• inhibiting proteasomes causes buildup killing cell
• cases peripheral neuropathy

• used in APL (acute promyelocytic leukemia)
• translocates 15 and 17: RAR+PML combine blocking cell maturation
• unblocks maturation allowing cell to differentiate into normal cells
• ATRA: cures it
• causes retinoic acid syndrome, shortness of breath

• promotes free radicals, induces maturation
• multiple myeloma, myelodysplasia, acute leukemia