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Corso Integrato di Clinica Medica ONCOLOGIA MEDICA AA 2009 - 2010 CYTOTOXIC AGENTS Prof. Alberto Riccardi The history of chemotherapy. I. The history of chemotherapy. II. * no. of approved new molecules for treatment of cancer by Food and Drug Administration (FDA) per 5 - yr period: relatively constant through 1990, and increased substantially since then CHEMOTHERAPEUTIC AGENTS USED FOR CANCER TREATMENT Chemotherapeutic agents used for cancer treatment * commonly used cancer chemotherapy agents grouped into 3 general categories: - affecting DNA; - affecting microtubules, and - molecularly targeted agents; * “usual doses” = tolerable and useful (specific dose for a particular pt # somewhat with particular treatment protocol or plan of treatment); - significant variation from these doses be carefully verified to avoid or anticipate toxicity DIRECT DNA - INTERACTIVE AGENTS Direct DNA - interactive agents. I. * DNA replication occurs during synthesis or S - phase of cell cycle, with chr segregation of replicated DNA occurring in M (mitosis) phase (G1 and G2 "gap phases”) precede S and M, respectively; - historically, chemotherapeutic agents divided into "phase nonspecific" (act in any phase of cell cycle) and "phase specific" (require cell at particular cell cycle phase to cause greatest effect); * once agent has acted, cells may progress to "checkpoints" in cell cycle where drug - related damage (e.g., double - strand breaks, DSBs) assessed, and either repaired or allowed to initiate apoptosis; - function of certain tumor - suppressor genes (e.g., p53) may be to modulate checkpoint function Direct DNA - interactive agents. II. Checkpoints * p53 - Binding Protein 1 (53BP1) - dependent checkpoint pathway (G1 cell cycle arrest) triggered by genotoxic events leading to double - strand breaks (DSBs); - epigenetic phosphorylation of histone H2AX to γ - H2AX by ATM (Ataxia Telangiectasia Mutated) occurs at or near site of DSBs and required for subsequent phosphorylation of 53BP1 by ATM and localization of 53BP1 into nuclear foci; - additionally, 53BP1 function critical for coupling ATM to many of its downstream targets, including tumor suppressor p53 and Structural Maintenance of Chromosomes protein 1 (SMC - 1); * in case of Chk2 kinase (G2 chechpoint activation), coupling mechanism to ATM independent of 53BP1 Direct DNA - interactive agents. III. p53 * with a G1 cell having low level of DNA damage, p53 protein hampers entering S phase and copy its DNA (→ → abnormal G1 cells undergo programmed cell death, i.e., apoptosis or growth arrest and DNA repair); * with a G1 cell having high level of DNA damage and mutant p53 → cell divides and undergoes clonal expansion, evolution and cancerization ALKYLATING AGENTS Alkylating agents. I. Formation of covalent DNA adducts * alkylating agents (= class of cell cycle phase - nonspecific agents) break down (either spontaneously or after normal organ or tumor cell metabolism) to reactive intermediates that covalently modify bases in DNA → cross - linkage of DNA strands or appearance of breaks in DNA, as result of repair efforts; * “broken" or “cross - linked” DNA intrinsically unable to complete normal replication or cell division (with being, in addition, potent activator of cell cycle checkpoints and further activates cell - signaling pathways precipitating apoptosis) Alkylating agents. II. * alkylating agents work by 3 # mechanisms, achieving same end result = disruption of DNA function and cell death: - 1st mechanism: alkylating agent (pink stars, above) attaches alkyl groups (small carbon compounds = pink triangles, middle) to DNA bases; - alteration → DNA fragmented by repair enzymes in attempts to replace alkylated bases (below); - alkylated bases prevent DNA synthesis and RNA transcription from affected DNA Alkylating agents. III. * 2nd mechanism = formation of cross - bridges (= bonds between atoms in DNA); - in process (middle), two bases (pink linkages) linked together by alkylating agent having two DNA binding sites; - bridges formed within single molecule of DNA (below) or cross - bridge may connect two different DNA molecules; - cross - linking prevents DNA from being separated for synthesis or transcription Alkylating agents. IV. * 3rd mechanism: induction of mispairing of nucleotides (purines = adenine, A, and guanine, G, and pyrimidines = thymine, T, and cytosine, C) leading to mutations; - in normal DNA double helix, A always pairs with T and G always pairs with C; - below, alkylated G bases may erroneously pair with T; - with altered pairing not corrected, it leads to permanent mutation Alkylating agents. V. Toxicity * all alkylating agents share similar toxicities: myelosuppression, alopecia, gonadal dysfunction, mucositis and pulmonary fibrosis; - may cause "second neoplasms", particuraly leukemia, many yrs after use (especially in low doses for protracted periods); - alkylating agents # greatly in spectrum of normal organ toxicities Alkylating agents. VI. Cyclophosphamide * inactive unless metabolized by liver to 4 - hydroxy cyclophosphamide, which decomposes into alkylating species and to chloroacetaldehyde and acrolein; - acrolein causes chemical cystitis (= hydration be maintained while using cyclophosphamide); - severe cystitis effectively treated with mesna (2 - mercapto ethanesulfonate) Alkylating agents. VII. Cyclophosphamide * sporadic interstitial pneumonitis (→ → pulmonary fibrosis); - cardiac dysfunction may occur with high doses cyclophosphamide (used in conditioning regimens for bone marrow transplant); * liver disease impairs drug activation Alkylating agents. VIII. Ifosfamide * ifosfamide = cyclophosphamide analogue more slowly activated in liver; - requires coadministration of mesna to prevent bladder injury; - central nervous system (CNS) effects, including somnolence, confusion and psychosis (related to low body surface area or presence of nephrectomy) ALKYLATING AGENTS. I. Drug Examples of usual doses Toxicity Interactions, issues Direct DNA - interacting agents Alkylatorsa Cyclophosphamide 400 - 2000 mg / m2 IV 100 mg / m2PO qd Marrow (relative platelet sparing) Cystitis Common alkylatora Cardiac (high dose) Liver metabolism required to activate to phosphoramide mustard + acrolein Mesna protects against "high - dose" bladder damage Ifosfamide 1.2 g / m2 / day qd x5 + mesna Myelosuppressive Bladder Neurologic Metabolic acidosis Neuropathy Isomeric analogue of cyclophosphamide More lipid soluble Greater activity vs testicular neoplasms and sarcomas Must use mesna a Common alkylator: myelosuppression, alopecia, pulmonary fibrosis, infertility and teratogenesis Alkylating agents. IX. Mechlorethamine * several alkylating agents less commonly used; * nitrogen mustard (mechlorethamine) decomposes rapidly in aqueous solution (to potentially yield a bifunctional carbonium ion); - be administered shortly after preparation into a rapidly flowing intravenous line (with moderate nausea); - aseptic thrombophlebitis frequent, even without infiltration; - used topically as a dilute solution in cutaneous lymphomas, with frequent hypersensitivity reactions Alkylating agents. IXbis. Mechlorethamine * powerful vesicant (infiltration symptomatically ameliorated by infiltration of affected site with 1 / 6 M thiosulfate) Alkylating agents. X. * chlorambucil → myelosuppression, azoospermia, nausea and pulmonary side effects; * busulfan → profound, late onset myelosuppression, alopecia and pulmonary toxicity (relatively "lymphocyte sparing“), with its routine use in treatment of CML curtailed by imatinib (Gleevec) or dasatinib; - still employed in transplant preparation regimens; * melphalan: variable oral bioavailability and undergoing extensive binding to albumin and alfa1 - acidic glycoprotein; - prominent activity in multiple myeloma ALKYLATING AGENTS. II. Drug Examples of usual doses Toxicity Interactions, issues Direct DNA - interacting agents Alkylatorsa Mechlorethamine 6mg / m2 IV day 1 and day 8 Marrow Vesicant Nausea Chlorambucil 1- 3 mg / m2 qd PO Marrow Common alkylatora Melphalan 8 mg / m2 qd x 5, PO Marrow (delayed nadir) GI (high dose) Topical use in cutaneous lymphoma Decreased renal function delays clearance a Common alkylator: myelosuppression, alopecia, pulmonary fibrosis, infertility and teratogenesis Alkylating agents. XI. Nitrosureas * carmustine (BCNU) breaks down to carbamoylating species that not only cause distinct pattern of DNA base pair - directed toxicity but also covalently modify proteins; - share relatively delayed bone marrow toxicity (possibly cumulative and long - lasting); - methyl CCNU (lomustine) → direct glomerular and tubular damage (related to dose and time of exposure) Alkylating agents. XIbis. Streptozotocin * streptozotocin unique, in that its glucose - like structure conveys specific toxicity to islet cells of pancreas (for whose derivative tumor types prominently indicated) as well as causing renal toxicity as Fanconi syndrome (= amino aciduria, glycosuria and renal tubular acidosis) ALKYLATING AGENTS. III. Drug Examples of usual doses Toxicity Interactions, issues Direct DNA - interacting agents Alkylatorsa 200 mg / m2 IV 150 mg / m2 PO Marrow (delayed nadir) GI, liver (high dose) Renal Marrow Lomustine (CCNU) 100 - 300 mg / m2 PO (delayed nadir) Carmustine (BCNU) a Common alkylator: delayed myelosuppression, alopecia, pulmonary fibrosis, infertility and teratogenesis - - Alkylating agents. XII. * procarbazine metabolized in liver and possibly in tumor cells to yield a variety of free radical and alkylating species; - beside myelosuppression, it causes hypnotic and other CNS effects, including vivid nightmares; - can cause disulfiram - like syndrome on ingestion of ethanol (disulfiram = drug used for treatment of chronic alcoholism by producing an acute sensitivity to alcohol = hangover, flushing of skin, accelerated heart rate, shortness of breath, nausea, vomiting, headache. visual disturbances, mental confusion, postural fainting ± circulatory collapse); * altretamine (formerly hexamethyl - melamine) and thiotepa give rise to alkylating species (nature of DNA damage not well characterized); - thiotepa used for intrathecal treatment of neoplastic meningitis Alkylating agents. XIII. Dacarbazine * dacarbazine (DTIC) activated in liver to yield highly reactive methyl diazonium cation; - only modest myelosuppression 21 - 25 days after a dose but prominent nausea on day 1; - temozolomide structurally related to dacarbazine but designed to be activated by nonenzymatic hydrolysis in tumors and bioavailable orally ALKYLATING AGENTS. IV. Drug Examples of usual doses Toxicity Interactions, Issues Direct DNA - interacting agents Alkylatorsa Dacarbazine 375 mg / m2 IV day 1 and day 15 Marrow Nausea Flulike Metabolic activation Procarbazine 100 mg / m2 / day qd x14 Marrow Nausea Neurologic Common alkylatora Liver and tissue metabolism required Disulfiran - like effect with ethanol Acts as MAOI HBP after tyrosine - rich foods a Common alkylator: modest myelosuppression, alopecia, pulmonary fibrosis, infertility and teratogenesis MAOI = monoamine oxidase inhibitors; HBP = high blood pressure ALKYLATING AGENTS. V. Drug Examples of usual doses Toxicity Interactions, issues Direct DNA - interacting agents Alkylators Temozolomide 150 - 200 mg / q28d or 75 mg / m2qd x6 - 7 vks Altretamine (formerly 260 mg / m2 / day qd x 14 - 21 as 4 divided oral hexa - methyl doses melamine) Nausea / vomiting Headache / fatigue Constipation Infrequent myelosuppression Nausea Neurologic (mood swing) Neuropathy Marrow (less) Liver activation Barbiturates enhance / cimetidine diminishes Alkylating agents. XIV. Cisplatin * cisplatin discovered fortuitously by observing that bacteria in electrolysis solutions could not divide; - only cis diamine configuration active as antitumor agent (hypothesized that in intracellular environment, chloride is lost from each position, being replaced by a water molecule, with resulting positively charged species being efficient bifunctional interactor with DNA, forming “Pt - based cross - links”) Alkylating agents. XV. Platin derivatives Purine synthesis Pyrimidine synthesis Ribonucleotides “adducts” formed with DNA Deoxyribonucleotides transcription and replication inhibited by formation of mainly intrastrand crosslinks DNA RNA (transfer, messenger, ribosomal) NH3 G Pt Proteins Enzymes Microtubules NH3 G Alkylating agents. XVI. Cisplatin * cisplatin requires administration with adequate hydration, including forced diuresis with mannitol to prevent kidney damage (even with hydration, gradual ↓ in kidney function common, along with noteworthy anemia); - hypomagnesemia frequently occurs → hypocalcemia and tetany; - myelosuppression less common than with other alkylating agents; - chronic vascular toxicity (Raynaud's phenomenon, coronary artery disease) as unusual toxicity Alkylating agents. XVIbis. Cisplatin * other common toxicities include neurotoxocity (with stocking - and - glove sensorimotor neuropathy) and hearing loss (in 50% of pts treated with conventional doses); * intensely emetogenic, requiring prophylactic antiemetics Alkylating agents. XVII. Carboplatin and oxaliplatin * with carboplatin, less nephro -, oto and neurotoxicity; - myelosuppression more frequent; - as drug exclusively cleared through kidney, adjustment of dose for creatinine clearance accomplished through use of various dosing nomograms; * oxaliplatin = platinum analog with noteworthy activity in colon cancers refractory to other treatments; - prominently neurotoxic ALKYLATING AGENTS. VI. Drug Examples of usual doses Toxicity Interactions, issues Direct DNA - interacting agents Alkylators Cisplatin 20 mg / m2 qd x 5 IV 1 q 3 - 4 vks or 100–200 mg / m2 / dose IV q3–4 vks Nausea Maintain high urine flow; Neuropathy osmotic diuresis, monitor Auditory intake / output K+, Mg2+ Marrow platelets > WBCs Emetogenic - prophylaxis Renal Mg2+, Ca2+ needed Full dose if CrCl > 60 mL / min and tolerate fluid push Carboplatin 365 mg / m2IV q 3 - 4 vks as adjusted for CrCl Marrow platelets > WBCs Reduce dose according to Nausea CrCl: to AUC of 5 – 7 mg / Renal (high dose) mL / min [AUC = dose / (CrCl + 25)] Oxaliplatin 130 mg / m2q 3wks over 2h or 85 mg / m2 q 2vks Nausea Anemia Acute reversible neurotoxicity; chronic sensory neurotox icity cumulative with dose; reversible laryngopharyngeal spasm CrCl, creatinine clearance; AUC, area under the curve ANTITUMOR ANTIBIOTICS Antitumor antibiotics * antitumor antibiotics produced by bacteria that in nature appear to provide chemical defense against hostile microorganisms; - bind to DNA directly and frequently undergo electron transfer reactions to generate “free radicals” (= atoms, molecules or ions, on open shell configuration, with unpaired electrons causing them to be highly chemically reactive) in close proximity to DNA → “oxidative stress” (caused by imbalance between production of reactive oxygen and biological system's ability to detoxify reactive intermediates or easily repair resulting damage) → DNA damage in form of “single - strand breaks” or “cross - links” Antitumor antibiotics and free radicals * = atoms, molecules or ions, on open shell configuration, with unpaired electrons causing them to be highly chemically reactive ANTITUMOR ANTIBIOTICS TOPOISOMERASE POISONS Antitumor antibiotics. I. Topoisomerase poisons. I. * topoisomerase enzimes relax torsionally strained DNA (supercoiled, important for DNA packaging within cell) allowing DNA double helix to separate and replicate; - subsequently religates cleaved strands; - topoisomerase poisons = natural products or semisynthetics derived from plants modifying enzymes (topoisomerases) regulating capacity of DNA to “unwind” and “religate” allowing normal replication or transcription Antitumor antibiotics. II. Topoisomerases. II. * topoisomerase I: creates “single - strand breaks” that then rejoin following passage of other DNA strand through break (in S - phase, topoisomerase I - induced, not promptly resealed breaks lead to progress of replication fork off end of DNA strand → DNA damage is potent signal for induction of apoptosis); - topoisomerase II: creates “double - strand breaks” through which another segment of DNA duplex (double stranded DNA) passes before rejoining Antitumor antibiotics. IIbis. Topoisomerase poisons. IIbis. * topoisomerase I inhibitors (derivatives of camptothecin, a Chinese tree) responsible for unwinding DNA strand by introducing “single - strand breaks” and allowing rotation of one strand about other = promote stabilization of DNA linked to topoisomerase I in so - called “cleavable complex”; - etoposide: analogous action with topoisomerase II Antitumor antibiotics. III. Topoisomerase I poisons. I. Topo 1 inhibitor Excessive torsion of DNA DNA replication Cutting step Topo 1 action Relaxation Closing step Closing step inhibition Cell death Antitumor antibiotics. IIIbis. Topoisomerase poisons. Ibis a b * a) normally, topoisomerase I introduces a nick in DNA backbone (so - called “cleavable complex”) allowing rotation of one strand around other, thus releasing torsional strain which otherwise accumulates in front of advancing replication fork (large arrow); - DNA break extremely transient and religated almost immediately at same time that topoisomerase I releases other strand; * b) poison drug (e.g., irinotecan, black oval with C) binds to topoisomerase I nicked DNA complex (so - called “cleavable complex”), preventing religation of nicked strand and release of enzyme; [- eventually, replication fork collides with complex, causing formation of double - strand break] Antitumor antibiotics. IV. Topoisomerase I poisons. III. * owing role of topoisomerase I in procession of replication fork, topoisomerase I poisons cause lethality if topoisomerase I - induced lesions made in S - phase; (- DNA damage in any cell cycle phase, but cells with p53 and Rb pathway lesions tend to arrest in S - phase or G2 of cell cycle, as result of defective checkpoint mechanisms) Antitumor antibiotics. V. Topoisomerase I poisons. IV. Camptothecin derivatives * two camptothecin derivatives approved and used in cancer chemotherapy: * topotecan, in gynecologic tumors and small cell lung cancer; - toxicity limited to myelosuppression and mucositis; * irinotecan (CPT - 11), in colon carcinoma; - in addition to myelosuppression, it causes secretory diarrhea (related to toxicity of metabolite SN - 38) effectively treated with loperamide or octreotide Antitumor antibiotics. VI. Topoisomerase II poisons. I. Etoposide. I. * synthetically derived from plant product podophyllotoxin, it binds directly to topoisomerase II and DNA in reversible ternary complex; - stabilizes covalent intermediate in enzyme's action where enzyme is covalently linked to DNA (historically, this "alkali - labile" DNA bond = first hint that enzyme topoisomerase exists); - prominent G2 arrest, reflecting action of DNA damage checkpoint Antitumor antibiotics. VII. Mechanism of Topoisomerase II action. II. * Step 1: Topo II binds non covalently to gate (G) duplex (double - stranded DNA) (so called because it opens like a gate); - Step 2: G duplex - topo II complex binds at crossover region with transported (T) duplex (so called because this duplex passes through G duplex); - Step 3: ATP binds and promotes formation of tridimensional topological complex; - Step 4: Mg2+ - dependent cleavage of G duplex; - Step 5: T duplex passes through gap formed in G duplex; - Step 6: G duplex is re - ligated and bound ATP hydrolysed; - enzyme now free to enter another catalytic cycle Antitumor antibiotics. VIII. Topoisomerase II poisons. III. Etoposide. III. * prominent clinical effects include myelosuppression, nausea and transient hypotension (related to speed of administration); - mild vesicant, but relatively free from other large - organ toxicities; * with at high doses or very frequently, topoisomerase II inhibitors may cause mixed lineage secondary acute leukemia (MLL) associated with chr 11q23 abnormalities in up to 1% of exposed pts ANTITUMOR ANTIBIOTICS. I. TOPOISOMERASES POISONS Drug Examples of usual Toxicity doses Direct DNA – interacting agents Interactions, issues Antitumor antibiotics Topotecan Irinotecan (CPT 11) Etoposide (VP16 - 213) 20 mg / m2IV q3–4vks over 30 min or 1.5–3 mg / m2q3–4vks over 24 h or 0.5 mg / m2 / day over 21 days Marrow Mucositis Nausea Mild alopecia Reduce dose with renal failure No liver toxicity 100 - 150 mg / m2IV over 90 Diarrhea: "early onset" with Prodrug requires enzymatic min q3 - 4vks cramping, flushing, clearance to active drug"SN 2 or 30 mg / m / day over vomiting; "late onset" after 38" 120 h several doses Early diarrhea likely due Marrow tobiliary excretion Alopecia Late diarrhea, use "high Nausea dose" loperamide(2 mg q2 Vomiting 4h) Pulmonary 100–150 mg / m2IV qdx3–5d Or 50 mg / m2 PO qdx 21d or up to 1500 mg / m2 / dose (high dose with stem cell support) Marrow (WBCs > platelet) Alopecia Hypotension Hypersensitivity(rapid IV) Nausea Mucositis (high dose) Hepatic metabolism—renal 30% Reduce doses with renal failure Schedule - dependant (5 day better than 1 day) Late leukemogenic Accentuate antimetabolite action ANTITUMOR ANTIBIOTICS ANTHRACYCLINES Antitumor antibiotics. IX. Anthracyclines. I. * doxorubicin (Adriamycin®) intercalates into DNA, with altering DNA structure, replication and topoisomerase II function; - also, undergoes reduction reactions by accepting electrons into its quinone ring system, with capacity to undergo “reoxidation” and to form dangerous “reactive oxygen radicals” (ROS = reactive molecules containing oxygen atom, either as oxygen ions and peroxides) after reoxidation; * myelosuppression, alopecia, nausea, and mucositis; - acute cardiotoxicity in form of atrial and ventricular dysrhythmias (rarely of clinical significance) Antitumor antibiotics. X. Anthracyclines. II. * #, cumulative doses > 550 mg / m2 associated with 10% incidence of chronic cardiomyopathy [(incidence of cardiomyopathy related to schedule = peak serum concentration, with low dose (frequent treatment or continuous infusions) better tolerated than intermittent higher dose exposures)] Antitumor antibiotics. Xbis. Anthracyclines. IIbis. Pathway of anthracycline - induced chronic cardiac dysfunction * chronic cardiotoxicity related to iron - catalyzed oxidation (oxidative stress damage; ODFR, oxygen derived free radicals = ROS) ) and reduction of doxorubicin (not to topoisomerase action) Antitumor antibiotics. Xter. Anthracyclines. IIter. * doxorubicin's cardiotoxicity ↑ when given together with trastuzumab (Herceptin, anti - HER - 2 / neu Ab); - radiation recall or interaction with concomitantly administered radiation frequently cause local site complications Antitumor antibiotics. XI. Anthracyclines. III. * powerful vesicant, with necrosis of tissue at 4 - 7 days after extravasation; - be administered into rapidly flowing intravenous line, with dexrazoxane (Cardioxane©) being antidote to doxorubicin - induced cardiotoxicity and extravasation (it chelates iron, but precise protection mechanism not known); doxorubicin extravasation - doxorubicin metabolized by liver (doses ↓ by 50 - 75% with liver dysfunction) Antitumor antibiotics. XII. Anthracyclines. IV. * daunorubicin© closely related to doxorubicin and actually introduced first into leukemia treatment (preferable to doxorubicin owing to less mucositis and colonic damage); * idarubicin© also used in acute myeloid leukemia and preferable to daunorubicin in activity Antitumor antibiotics. XIII. Anthracyclines. V. * encapsulation of daunorubicin into liposomal formulation attenuates cardiac toxicity and antitumor activity (e.g., in Kaposi's sarcoma and ovarian cancer) * liposome = tiny bubble (vesicle), made out of same material as cell membrane, can be filled with drugs and used to deliver drugs for cancer and other diseases; - membranes usually made of phospholipids (= molecules having a head and a tail group), with head attracted to water and tail (made of long hydrocarbon chain) repelled by water Antitumor antibiotics. XIV. Mitoxantrone. I. * mitoxantrone (mainly topoisomerase II inhibitor, also disrupting DNA repair) = synthetic compound designed to recapitulate features of doxorubicin but with less cardiotoxicity (comparing ratio of cardiotoxic to therapeutic effective doses); - still associated with 10% incidence of cardiotoxicity at cumulative doses of > 150 mg / m2; - alopecia Antitumor antibiotics. XV. Mitoxantrone. II * cases of acute promyelocytic leukemia (APL) shortly after exposure of pts to mitoxantrone (especially in adjuvant treatment of breast cancer); - while chemotherapy - associated leukemia generally of acute myeloid type, APL (acute promyelocytic leukemia) arising after mitoxantrone has typical 15;17 chr translocation (with breakpoints of translocation at topoisomerase II sites, preferred sites of mitoxantrone action, clearly linking action of drug to leukemia) ANTITUMOR ANTIBIOTICS. II. ANTHRACYCLINES Drug Examples of usual doses Toxicity Interactions, issues Direct DNA - interacting agents Antitumor antibiotics Doxorubicin and daunorubicin 45 – 60 mg / m2 dose q 3–4 vks or 10– 30 mg / m2dose q week or continuous - infusion regimen Marrow Mucositis Alopecia Cardiovascular acute / chronic Vesicant Heparin aggregate; coadministration increases clearance Acetaminophen, BCNU increases liver toxicity Radiation recall Idarubicin 10 – 15 mg / m2 IV q3vks or 10 mg / m2 IV qdx3 Marrow Cardiac (less than doxorubicin) None established Epirubicin 150 mg / m2 IV q3vks Marrow Cardiac None established Mitoxantrone 12 mg / m2 qd x3 or 12–14 mg / m2 q3 wks Marrow Cardiac (less than doxorubicin) Vesicant (mild) Blue urine, sclerae, nails Interacts with heparin Less alopecia, nausea than doxorubicin Radiation recall Antitumor antibiotics. XVI. Bleomycin. I. * bleomycin = mixture of glycopeptides (mainly from bacterium Streptomyces verticillus) with unique feature of forming complexes with Fe2+ while also bound to DNA; - oxidation of Fe2+ gives rise to superoxide and hydroxyl radicals; - cleared rapidly, but augmented skin and pulmonary toxicity in presence of renal failure → doses reduced by 50 - 75% when creatinine clearance < 25 mL / min; - not vesicant (administered intravenously, intramuscularly or subcutaneously) Antitumor antibiotics. XVII. Bleomycin. II. * little, if any, myelosuppression; - common side effects include fever and chills, facial flush, Raynaud's phenomenon and hyperpigmentation of skin; - hypertension can follow rapid iv administration; - incidence of anaphylaxis with early preparations of drug → administering test dose of 0.5 - 1 unit before rest of dose Antitumor antibiotics. XVIII. Bleomycin. II. * bleomycin inactivated by bleomycin hydrolase, whose concentration ↓ in skin (hyperpigmentation) and lung (pulmonary fibrosis) Antitumor antibiotics. XIX. Bleomycin. IV. * pulmonary fibrosis = most feared complication of bleomycin treatment (↑ ↑ incidence at > 300 cumulative units administered and minimally responsive to treatment, e.g., with glucocorticoids); - earliest indicator of adverse effect = ↓ in DLCO (Diffusing capacity of Lung for Carbon monoxide), but cessation of drug immediately its documentation not prevents further decline in pulmonary function Antitumor antibiotics. XX. Bleomycin. V. * because bleomycin - dependent electron transport dependent on O2, bleomycin toxicity may become apparent after exposure to transient very high PIO2 (= Partial pressure of Inspired Oxygen); - during surgical procedures, pts with prior exposure to bleomycin be maintained on lowest PIO2 consistent with maintaining adequate tissue oxygenation Antitumor antibiotics. XXI. Mytomicin C * mitomycin C (undergoing reduction of its quinone function) generates a bifunctional DNA alkylating agent; - broadly active antineoplastic agent with a no. of unpredictable toxicities, including delayed bronchospasm (12 14 h after dosing) and chronic pulmonary fibrosis (more frequent at doses of 50 - 60 mg / m2); - cardiomyopathy may occur, especially after prior radiation therapy; - notable vesicant and causes substantial nausea and vomiting; * used for intravesical instillation for curative treatment of superficial transitional bladder carcinomas and, with radiation therapy, for curative treatment of anal carcinoma Antitumor antibiotics. XXIbis. Mytomicin C * hemolytic / uremic syndrome (hemolytic anemia, thrombocytopenia and acute renal failure) with ultimate mortality rate of 25 - 50% (poorly treated by conventional component support and exchange transfusion) ANTITUMOR ANTIBIOTICS. III. VARIOUS Drug Examples of usual Toxicity doses Direct DNA - interacting agents Interactions, issues Antitumor antibiotics Bleomycin 15–25 mg / dq dx 5 IV bolus or continuous IV Pulmonary Skin effects Raynaud's Hypersensitivity Inactivate by bleomycin hydrolase (decreased in lung / skin) O2 enhances pulmonary toxicity Cisplatin - induced decrease in CrCl may increase skin / lung toxicity Reduce dose if CrCl < 60 mL / min Actinomycin D 10–15 g / kg / day qdx5 IV bolus Marrow Nausea Mucositis Vesicant Alopecia Radiation recall Mitomycin C 6–10 mg / m2q6 vks Marrow Vesicant Hemolytic - uremic syndrome Lung CV - heart failure Treat superficial bladder cancers by intravesical infusion Delayed marrow toxicity Cumulative marrow toxicity CrCl, creatinine clearance; CV, cardiovascular ANTIMETABOLITES Antimetabolites. I. * “broad” definition of antimetabolites = compounds with structural similarity to precursors of purines or pyrimidines, or compounds interfering with purine or pyrimidine synthesis; - cause DNA damage indirectly, through misincorporation into DNA, abnormal timing or progression through DNA synthesis or altered function of pyrimidine and purine biosynthetic enzymes; - greatest toxicity to cells in S - phase and degree of toxicity ↑ with duration of exposure; - common toxic effects include stomatitis, diarrhea and myelosuppression (second malignancies not associated) METHOTREXATE Antimetabolites. II. Methotrexate. I. * both reduced folates [substrates = coemzymes in a no. of single - carbon transfer reactions, e.g., involved in synthesis of dTMP (2 - deoxythymidine - 5 - phosphate) from dUMP (2’ - deoxyuridine - 5 phosphate)] and methotrexate (antifolate drug) transported into cells by folate carrier; - methotrexate ↓ dihydrofolate reductase, which regenerates reduced folates from oxidized folates (produced when thymidine monophosphate, dTMP, formed from deoxyuridine monophosphate, dUMP); - without reduced folates, cells die ("thymine - less" death) Antimetabolites. III. Methotrexate. II. * methotrexate (MTX) enters cell through reduced folate carrier (a) using an endocytic pathway activated by folate receptor (b); - after entering cell, methotrexate is polyglutamated (Glu) by enzyme folyl polyglutamate synthase (C); - methotrexate and its polyglutamates ↓ enzyme dihydro - folate reductase (d), blocking conversion of dihydrofolate (FH2) to tetrahydrofolate (FH4, coenzyme in many reactions, especially in metabolism of nucleic acids); - as tetrahydrofolate stores depleted, ↓ thymidylate (TMP) synthesis (e) and, ultimately, ↓ DNA synthesis (f); - long - chain polyglutamates of MTX = same affinity as MTX for target enzyme dihydrofolate reductase, but markedly ↑ inhibitory effects on both thymidylate synthesis (e) and purine biosynthesis (f), required for RNA production] Antimetabolites. IV. Methotrexate. III. * leucovorin = folinic acid (5 - formyl derivative of tetrahydrofolic acid = N5 - formyltetrahydrofolate) readily converted to other reduced folic acid derivatives, e.g. N5 - tetrahydrofolate (= without requiring dihydrofolate reductase conversion); → functioning as vitamin unaffected by inhibition of dihydrofolate reductase by drugs (e.g., MTX) → vitamin activity equivalent to folic acid; - this bypasses inhibition of dihydrofolate reductase and rescue cells from methotrexate damage, which is maintained in cells by polyglutamylation; * → therefore, folinic acid allows that some purine / pyrimidine synthesis occurs in presence of dihydro - folate reductase inhibition by methotrexate → some normal DNA replication and RNA transcription processes can proceed Antimetabolites. V. Methotrexate. IV. * from these properties, design of "high - dose" methotrexate regimens with leucovorin rescue of normal marrow and mucosa as part of curative approaches to osteosarcoma in adjuvant setting and hematopoietic neoplasms of children and adults Antimetabolites. VI. Methotrexate. V. * methotrexate cleared by kidney via both glomerular filtration and tubular secretion (toxicity ↑ by renal dysfunction and drugs undergoing tubular secretion, e.g., salicylates, probenecid and nonsteroidal anti inflammatory agents); - with normal renal function, 15 mg / m2 leucovorin will rescue 10–8 to 10–6 M methotrexate in 3 - 4 doses (with ↓ creatinine clearance, leucovorin doses of 50 - 100 mg / m2 continued until methotrexate levels < 5 x 10–8 M) Antimetabolites. VII. Methotrexate. VI. * in addition to bone marrow suppression and mucosal irritation, methotrexate can cause renal failure itself at high doses owing to crystallization in renal tubules (→ → high - dose regimens require alkalinization of urine with ↑ flow by hydration); * methotrexate sequestered in third - space collections (e.g., pleural effusions or ascitic fluids) and leech back into general circulation (→ → prolonged myelosuppression); - less frequent adverse effects include reversible ↑ in transaminases and hypersensitivity - like pulmonary syndrome; * chronic low - dose can cause hepatic fibrosis; * when administered to intrathecal space, methotrexate can cause chemical arachnoiditis and CNS dysfunction Antimetabolites. VIII. Pemetrexed * pemetrexed = novel, "multitargeted" folate - directed antimetabolite = ↓ activity of several enzymes, including dihydrofolate reductase, thymidylate synthetase and glycinamide ribonucleotide formyltransferase → affects synthesis of both purine and pyrimidine nucleic acid precursors of both RNA and DNA; - to avoid significant toxicity to normal tissues, pts receive low - dose folate and vitamin B12 supplementation; * activity against certain lung cancers and, in combination with cisplatin, also against mesotheliomas 5 - FLUORURACIL uracil 5 - fluouracil Antimetabolites. IX. 5 - fluorouracil. I. * 5 - fluorouracil (5 - FU) = early example of "rational" drug, from observation that tumor cells incorporate radiolabeled uracil more efficiently into DNA than normal cells, especially in gut; - 5 - FU metabolized in cells to 5 - fluorouridine - 5‘ monophosphate (FUMP), which (via # enzymatic reactions) inhibits RNA and DNA synthesis, either by incorrectly incorporating “false” bases into RNA and / or DNA or inhibiting DNA thymidylate synthetase (TS); * in addition, misincorporation leads to single - strand breaks and RNA can aberrantly incorporate FUMP (5 - fluorouridine - 5‘ - monophosphate) and / or its derivatives; * 5 - FU metabolized by dihydro - pyrimidine dehydrogenase (DPD) → deficiency of enzyme → excessive toxicity from 5 - FU Antimetabolites. X. 5 - fluorouracil. II. * actually, 5 - FU converted into 3 main active metabolites: - fluorodeoxyuridine monophosphate [FUMP → fluorouridine diphosphate (FUDP) → active metabolite fluorouridine triphosphate (FUTP) → RNA damage via FUTP interfering with RNA synthesis]; - fluorodeoxyuridine monophosphate [FUMP → fluorodeoxyuridine triphosphate (FUDP) → fluorodeoxyuridine diphosphate (FdUDP) → fluorodeoxyuridine monophosphate (FdUMP) → DNA damage via inhibition of thymidylate synthetase], and - fluorodeoxyuridine monophosphate [FUMP → fluorouridine diphosphate (FUDP) → fluorodeoxyuridine diphosphate (FdUDP) → fluorodeoxyuridine triphosphate (FdTDP) → DNA damage via FdUTP interfering with DNA synthesis) Antimetabolites. XI. 5 - fluorouracil. III. * main mechanism of 5 - FU activation = conversion to fluorouridine monophosphate (FUMP, inhibiting thymidilate synthase) (black), either directly by orotate phosphoribosyl - transferase (OPRT, with phosphoribosyl pyrophosphate, PRPP, as cofactor) or indirectly via fluorouridine (FUR) through actions of uridine phosphorylase (UP) and uridine kinase (UK); - FUMP then phosphorylated to fluorouridine diphosphate (FUDP) (red), further phosphorylated to RNA - active metabolite fluorouridine triphosphate (FUTP) (black) or converted to fluorodeoxyuridine diphosphate (FdUDP) (red) by ribonucleotide reductase (RR); - in turn, FdUDP either be phosphorylated or dephosphorylated to generate active metabolites FdUTP (interfering with DNA synthesis) and FdUMP (still interfering with thymidilate synthase), respectively Antimetabolites. XII. 5 - fluorouracil. IV. * an alternative activation pathway involves thymidine phosphorylase (TP), catalyzin conversion of 5 - FU to fluorodeoxyuridine (FUDR) → phosphorylated by thymidine kinase (TK) to FdUMP; * dihydro - pyrimidine dehydrogenase (DPD) - mediated conversion of 5 - FU to dihydrofluorouracil (DHFU) = rate limiting step of 5 - FU catabolism in normal and tumor cells (up to 80% of administered 5 - FU broken down by DPD in liver) Antimetabolites. XIII. 5 - fluorouracil. V. Inhibition of DNA synthesis via inhibition of thymidilate synthetase * normally (red), in presence of cofactor 5, 10 - methylene tetrahydrofolate (as methyl donor), thymidilate syntetase (TS) and 2’ deoxy - uridine - 5’ - mono - phosphate (dUMP) form ternary complex, enabling transfer of methyl group on ‘5 of dUMP to form thymidine - 5’ monophosphate (dUMP → dTMP); - following 5 - FU and 5 - FdUMP formation (black), methyl transfer does not occurs (F atom in C5 of 5 - FdUMP > tightly bound than H) → enzyme trapped in slowly reversible ternary complex; = blocked formation of dTMP and availability of thymidine - 5’ triphosphate (dTTP) for DNA replication and repair ("genotoxic stress" resulting from TS inhibition activates programmed cell death pathways) Antimetabolites. XIV. 5 - fluorouracil. VI. Inhibition of RNA synthesis * 5 - FUTP: due to comparable size F atom replacing H on ‘5 of uracil, 5 - FUTP fluoronucleotide mimics UTP, is recognized by RNA polymerases and 5 FU is incorporated in all classes of RNA (full cytotoxicity stems from a combination of numerous modifications of RNA, rather than alteration of single function) Antimetabolites. XII. 5 - fluorouracil. V. Antimetabolites. XVI. 5 - fluorouracil. VIII. * iv administration of 5 - FU → bone marrow suppression after short infusions and stomatitis after prolonged infusions; - less frequent toxicities include CNS dysfunction (prominent cerebellar signs) and endothelial toxicity (thrombosis, including pulmonary embolus and myocardial infarction); * leucovorin (folinic acid) ↑ activity of 5 - FU by promoting formation of ternary covalent complex of 5 - FU, reduced folate and TS Antimetabolites. XVII. 5 - fluorouracil. IX. Calcium folinate (leucovorin) * administration of IV 5 FU and folinic acid (leucovorin) ↑ efficacy (by ↑ binding of 5 - FU to its target enzyme, thymidylate synthase), with ↑ in cancer responses Antimetabolites. XVII. 5 - fluorouracil. IX. Calcium folinate (leucovorin) * administration of IV 5 - FU and folinic acid (leucovorin) ↑ efficacy (by ↑ binding of 5 - FU to its target enzyme, thymidylate synthase), with 3 fold ↑ in partial responses ORAL FLUOROPYRIMIDINES Antimetabolites. XVIII. Capecitabine. I. * oral bioavailability of 5 - FU varies unreliably, but developed, orally administered analogues of 5 - FU (e.g., capecitabine) allow at least equivalent activity to many parenteral 5 - FU - based approaches to refractory cancers Antimetabolites. XIX. Capecitabine. II. intestine capecitabine liver capecitabine tumor CE - not metabolized by thymidine phosphorylase in intestine, with ↓ GI toxicity; - activated to 5 - FU preferentially in tumors; 5‘ - DFCR CyD 5‘ - DFUR 5‘ - DFCR CyD 5‘ - DFUR thymidine phosphorylase 5 - FU * after passing intestine as intact molecule, converted: 1) to 5´ ´- deoxy - 5fluorocytidine (5’ - DFCR) by carboxylesterase (CE, almost exclusively in liver); 2) to 5´ ´- deoxy - 5 - fluorouridine (5’ - DFUR) by cytidine deaminase (CyD, high concentrations in liver and various solid tumors), and 3) to 5 - FU in tumors by thymidine phosphorylase (TP, > in tumors than in normal tissues) ANTIMETABOLITES. I. Drug Examples of Toxicity Interactions, usual doses issues Indirect DNA - interacting agents Antimetabolites Methotrexate 15 – 30 mg PO or IM qd x 3 – 5 or 30 mg IV days 1 and 8 or 1.5 – 12 g / m2 / day (with leucovorin) Marrow Liver / lung Renal tubular Mucositis Rescue with leucovorin Excreted in urine Decrease dose in renal failure NSAIDs increase renal toxicity Pemetrexed 200 mg / m2 q3 vks Anemia Neutropenia Thrombocytopenia 5 - Fluorouracil 375 mg / m2IV qd x5 or 600 mg / m2IV days 1 and 8 Marrow Mucositis Neurologic Skin changes Supplement folate / B12 Caution in renal Toxicityfailure enhanced by Capecitabine leucovorin Dihydropyrimidine dehydrogenase deficiency increases toxicity Metabolized in tissues 665 mg / m2 bid Diarrhea Prodrug of 5 - FU due continuous; Hand - foot syndrome to intratumoral 2 1250 mg / m bid 2 vks metabolism on / 1 off; 829 mg / m2 bid 2 vks on / 1 off + 60 mg / leucovorin Antimetabolites. XX. Cytosine arabinoside * cytosine arabinoside (Ara - C) incorporated into DNA (after formation of ara - CTP = arabino - furanosylcytosine triphosphate) → S - phase - related toxicity (especially used in hematologic malignancies); - maximal efficiency from continuous infusion schedules, with uptake maximal at 5 - 7 micro M; - can be administered intrathecally; * adverse effects include nausea, diarrhea, stomatitis, chemical conjunctivitis and cerebellar ataxia cytarbine arabinose sugar replacing ribose in cytidine (left) Antimetabolites. XXI. Gemcitabine * gemcitabine = cytosine derivative similar to Ara - C , incorporated into DNA after anabolism to triphosphate, rendering DNA susceptible to breakage and repair synthesis; - # from Ara - C, gemcitabine induced lesions very inefficiently removed; - # from Ara - C, useful activity in solid tumors, with limited non myelosuppressive toxicities Antimetabolites. XXII. 6 - thioguanine and 6 - mercaptopurine * 6 - thioguanine and 6 - mercaptopurine (6 - MP) for acute myeloid leukemia; - administered orally with variable bioavailability (6 - MP metabolized by xanthine oxidase, requiring dose reduction when used with allopurinol) ANTIMETABOLITES. II. Drug Examples of Toxicity usual doses Indirect DNA - interacting Agents Interactions, Issues Antimetabolites Cytosine arabinoside 100 mg / m2 / day qd x 7 Marrow Enhances activity of by continuous infusion Mucositis alkylating agents 2 or 1 – 3 g / m dose IV Neurologic (high dose) Metabolized in tissues by bolus Conjunctivitis (high dose) deamination Non cardiogenic pulmonary edema Gemcitabine 1000 mg / m2 IV weekly x7 Marrow Nausea Hepatic Fever / "flu syndrome" 6 - mercaptopurine 75 mg / m2 PO or up 500 mg / m2 PO (high dose) Marrow Liver Nausea Variable bioavailability Metabolized by xanthine oxidase Decrease dose with allopurinol Increased toxicity with thiopurine methyltransferase deficiency 6 - thioguanine 2–3 mg / kg / day for up to 3–4vks Marrow Liver Nausea Variable bioavailability Increased toxicity with thiopurine methyltransferase deficiency Antimetabolites. XXIII. Fludarabine phosphate and 2 - chlorodeoxyadenosine * fludarabine phosphate = prodrug of F - adenine arabinoside (F ara - A) designed to ↓ susceptibility of ara - A to adenosine deaminase; - F - ara - A incorporated into DNA, with delayed cytotoxicity even in cells with low growth fraction (e.g., chronic lymphocytic leukemia and follicular B cell lymphoma); - CNS and peripheral nerve dysfunction and myelosuppression (with T cell depletion and possible opportunistic infections); * 2 - chlorodeoxyadenosine = similar compound (activity in hairy cell leukemia) Antimetabolites. XXIV. 2 - deoxycoformycin and hydroxyurea * 2 - deoxycoformycin inhibits adenosine deaminase, with resulting ↑ in dATP levels → inhibition of ribonucleotide reductase as well as ↑ susceptibility to apoptosis, particularly in T cells; - renal failure and CNS dysfunction notable toxicities, in addition to immunosuppression; * hydroxyurea inhibits ribonucleotide reductase, resulting in S - phase block; - orally bioavailable and useful for acute management of myeloproliferative states ANTIMETABOLITES. III. Drug Examples of Toxicity Interactions, usual doses issues Indirect DNA - interacting agents Antimetabolites Fludarabine phosphate 25 mg / m2IV qd x5 Marrow Neurologic Lung Dose reduction with renal failure Metabolized to F– ara converted to F– ara ATP in cells by deoxycytidine kinase 2 - chloro - deoxy - adenosine 0.09 mg / kg / day qd x7 as continuous infusion Marrow Renal Fever Notable use in hairy cell leukemia Deoxycoformycin 4mg / m2IV every other wk Nausea Immunosuppression Neurologic Renal Excreted in urine Reduce dose for renal failure Inhibits adenosine deaminase Hydroxyurea 20–50 mg / kg (lean body weight) PO qd or 1–3 g / d Marrow Nausea Mucositis Skin changes Rare renal, liver, lung, CNS Decrease dose with renal failure Augments antimetabolite effect ANTIMETABOLITES. IV. Drug Examples of Toxicity Interactions, usual doses issues Indirect DNA - interacting agents Antimetabolites Azacytidine 750 mg / m2 / week or 150–200 mg / m2 / dayx 5–10 (bolus) or (continuous IV) Marrow Nausea Liver Neurologic Myalgia Use limited to leukemia Altered methylation of DNA alters gene expression Azathioprine 1 - 5 mg / kg / day Marrow Nausea Liver Metabolized to 6MP, therefore reduce dose with allopurinol Increased toxicity with thiopurine methyltransferase deficiency Antimetabolites. XXV. Asparaginese. I. * asparaginase = bacterial enzyme causing breakdown of extracellular asparagine required for protein synthesis in certain leukemic cells → effectively stops tumor cell DNA synthesis, as it requires concurrent protein synthesis → outcome of asparaginase action therefore very similar to result of small - molecule antimetabolites Antimetabolites. XXVI. Asparaginese. II. * being foreign protein, hypersensitivity reactions common, as effects on organs such as pancreas and liver that normally → ↓ insulin secretion with require continuing protein synthesis (→ hyperglycemia, ± hyperamylasemia and clotting function abnormalities → close monitoring of clotting functions accompany use of asparaginase); - paradoxically, owing to depletion of rapidly turning over anticoagulant factors, thromboses particularly affecting CNS also seen with asparaginase ANTIMETABOLITES. V. Drug Examples of Toxicity usual doses Indirect DNA - interacting agents Interactions, issues Antimetabolites Asparaginase 25,000 IU / m2 q3–4 vks or 6000 IU / m2 / day qod for 3 - 4vks or 1000–2000 IU / m2 for 10–20 days Protein synthesis Clotting factors Glucose Albumin Hypersensitivity CNS Pancreatitis Hepatic Blocks methotrexate action MITOTIC SPINDLE INHIBITORS MITOTIC SPINDLE INHIBITORS. I. * microtubules = cellular structures forming mitotic spindle, composed of repeating noncovalent multimers of α - and β dimers of protein tubulin; - in interphase cells, responsible for cellular "scaffolding" along which various motile and secretory processes occur (“cytoskeleton”) MITOTIC SPINDLE INHIBITORS VINCA ALCALOIDS a | podophyllum peltatum (mayapple), producing podophyllotoxin, and b | catharanthus roseus (Vinca rosea or rosy periwinkle), producing Vinca alkaloids (vinblastine and vincristine) MITOTIC SPINDLE INHIBITORS. II. Vincristine. I. * vincristine (vinca alkaloid) binds to tubulin dimer → microtubules “disaggregated” → block of growing cells in M phase (but toxic effects in G1 and S - phase also evident) MITOTIC SPINDLE INHIBITORS. IIbis. Vincristine. Ibis. * vinca alkaloids bind to tubulin dimers (at specific recognition site on protein); - tubulin - drug complex able to form paracrystaline aggregates → ↓ concentration of dimers and pushes equilibrium between growth and shrinling of microtubules in favor of shrinking → cells treated with vinca alkaloids loose ability to progress through mitosis correctly because of poorly formed mitotic spindles → damaged cells then die MITOTIC SPINDLE INHIBITORS. III. Vincristine. II. * metabolized by liver (dose adjustment with hepatic dysfunction required); - powerful vesicant (infiltration treated by local heat and infiltration of hyaluronidase); * at clinically used iv doses, frequent chronic neurotoxicity (as glove - and - stocking neuropathy) MITOTIC SPINDLE INHIBITORS. IV. Vincristine. III. * acute neurotoxicity also includes jaw pain, paralytic ileus, urinary retention and syndrome of inappropriate antidiuretic hormone secretion (no myelosuppression) MITOTIC SPINDLE INHIBITORS. V. Vinblastine and vinorelbine * vinblastine similar to vincristine, but more myelotoxic (with more frequent thrombocytopenia and also mucositis and stomatitis); * vinorelbine: # in resistance patterns in comparison to vincristine and vinblastine; - it may be administered orally MITOTIC SPINDLE INHIBITORS. I. Drug Examples of usual Toxicity doses Indirect DNA - interacting agents Interactions, issues Antimitotic agents Vincristine 1 - 1.4 mg / m2 / wk Vesicant Marrow Neurologic GI: ileus / constipation; Bladder toxicity; SIADH Cardiovascular Hepatic clearance Dose reduction for bilirubin > 1.5 mg / dL Prophylactic bowel regimen Vinblastine 6 - 8 mg / m2 / week Vesicant Marrow Neurologic (less common but similar spectrum to other vincas) Hypertension Raynaud's Hepatic clearance Dose reduction as with vincristine Vinorelbine 15 - 30 mg / m2 / week Vesicant, marrow Allergic / bronchospasm (immediate) Dyspnea / cough (subacute) Neurologic (less prominent but similar spectrum to other vincas) Hepatic clearance MITOTIC SPINDLE INHIBITORS TAXANES produced by plants of genus Taxus MITOTIC SPINDLE INHIBITORS. VI. Taxanes * taxanes include paclitaxel and docetaxel; - # from vinca alkaloids (“disaggregating” microtubules), taxanes “stabilize” microtubules against depolymerization → "stabilized" microtubules function abnormally (not able to undergo normal dynamic changes of structure and function necessary for cell cycle completion); * among most broadly active antineoplastic agents for use in solid tumors, with evidence of activity in ovarian, breast and lung cancers and Kaposi's sarcoma; - administered iv MITOTIC SPINDLE INHIBITORS. VII. Paclitaxel * paclitaxel requires Cremophor (polyethoxylated castor oil) containing vehicle responsible for hypersensitivity reactions; - premedication with dexamethasone (20 mg orally or iv) 12 and 6 hrs before treatment, diphenhydramine (Benadryl®, 50 mg) and cimetidine (Tagamet®, 300 mg), both 30 min before treatment, ↓ but does not eliminate risk of hypersensitivity reactions to paclitaxel vehicle; - beside hypersensitivity reactions, myelosuppression, neurotoxicity (glove - and - stocking numbness) and paresthesia; - cardiac rhythm disturbances (most commonly asymptomatic bradycardia and, much more rarely, varying degrees of heart block) of poor clinical significance in most pts MITOTIC SPINDLE INHIBITORS. VII. Paclitaxel * protein - bound formulation of paclitaxel (called nab – paclitaxel, Abraxane®) at least equivalent antineoplastic activity and decreased risk of hypersensitivity reactions MITOTIC SPINDLE INHIBITORS. VIII. Docetaxel * docetaxel uses polysorbate 80 formulation, which can cause fluid retention (from vascular leak syndrome); - as paclitaxel, comparable degrees of myelosuppression and neuropathy; - hypersensitivity reactions (including bronchospasm, dyspnea, and hypotension) less frequent (to some degree in up to 25% of pts dexamethasone → premedication ± antihistamines frequently used); - rash (prominently as pruritic maculopapular rash affecting forearms, but also associated with fingernail ridging, breakdown, and skin discoloration) can occur; - stomatitis somewhat more frequent than with paclitaxel MITOTIC SPINDLE INHIBITORS. II. Drug Examples of Toxicity usual doses Indirect DNA - interacting agents Interactions, issues Antimitotic agents 135 – 175 mg / m2 / 24 - h infusion or 175 mg / m2/3 - h infusion or 140 mg / m2 / 96 - h infusion or 250 mg / m2 / 24 - h infusion plus G-CSF Hypersensitivity Marrow Mucositis Alopecia Sensory neuropathy CV conduction disturbance Nausea - infrequent Premedicate with steroids, H1 and H2 blockers Hepatic clearance Dose reduction as with vincas NAB - paclitaxel (protein bound) 260 mg / m2q 3vks Neuropathy Anemia Neutropenia Thrombocytopenia Caution in hepatic insufficiency Docetaxel 100 mg / m2 / 1 hr infusion q3 vks Hypersensitivity Fluid retention syndrome Marrow Dermatologic Sensory neuropathy Nausea - infrequent Some stomatitis Premedicate with steroids, H1 and H2 blockers Paclitaxel MITOTIC SPINDLE INHIBITORS. IX. Estramustine. I. * estramustine (Estracyt) derivative of estrogen (estradiol) with added nitrogen mustard - carbamate ester moiety (→ → alkylating antineoplastic agent with estrogen - induced specificity); - useful in neoplasms possessing estrogen receptors (without evidence of interaction with DNA); - surprisingly, drug causes metaphase arrest, by binding to microtubule associated proteins → abnormal microtubule function mechlorethamine estradiol estramustine MITOTIC SPINDLE INHIBITORS. X. Estramustine. II. * estramustine binds to estramustine - binding proteins (EMBPs), notably present in prostate tumors tissue (→ → used as oral formulation in pts with prostate cancer); - gastrointestinal and cardiovascular adverse effects related to estrogen moiety in ~ 10% of pts, including worsened heart failure and thromboembolic phenomena; - gynecomastia and nipple tenderness also occur MITOTIC SPINDLE INHIBITORS. III. Drug Examples of Toxicity Interactions, usual doses issues Indirect DNA - interacting agents Antimitotic agents Estramustine phosphate 14 mg / kg / d in 3 - 4 divided doses with water > 2 h after meals Avoid Ca2+ - rich foods Nausea Vomiting Diarrhea CHF Thrombosis Gynecomastia CHF, congestive heart failure -