Chemotherapy: p.1 of 5 Cancer Chemotherapy Basics - Cell cycle specific: Antimetabolites (S phase), Antibiotics (G2 phase), Podophyllin alkaloids (S/G2 phase), Plant alkaloids (M phase) Cell cycle non-specific: Alkylating agents, Antibiotics Death from cancer: 1012 neoplastic cells (~ 1 kg) Chemotherapeutic agents exhibit first order kinetics Adverse Effects - Bone Marrow Toxicity: leukopenia, thrombocytopenia, anemia o Maximum toxicity: 10-14 d.; Recovery: 21-28 d. o Nitrosurea has delayed toxicity (4-6 weeks) o Busulfan & Vinblastine are potent myelosuppressants o Bleomycin & steroids don’t have significant BM toxicity - Nausea & Emesis: generally self-limiting o Fear results in anticipatory vomiting o Can be ameliorated by centrally-acting antiemetics (steroids, NK-1 antagonists, 5-HT 3 antagonists, BDZ) o Acute: works within the BBB (CNS stimulation of the vomiting center or CTZ); with alkylating agents (severe with Cisplastin) Begins: 4-6 hrs., lasts 1-2 d. o Delayed: effects on GI (death of mucosal cells stimulates the Vagus & Splanchnic nerves CTZ); severe with antimetabolites & bleomycin Begins: 2-6 d. - Alopecia o Severe with doxorubicin, cyclophosphamide, vincristine & methotrexate - Gonads - Fetus - Wounds - Delayed effects o Toxicity affecting the heart, lungs & kidney o Secondary cancers (Alkylating agents lesions in DNA) Alkylating Agents -- Cell cycle nonspecific Drugs Actions DNA strand breakage - Intramolecular cyclization forms electrophilic reactive ion, which transfers an alkyl Mechlorethamine group to guanine residues on DNA - Depurination by excision of guanine residues Prodrug activated by P450 to aldophosphamide: in target cell, broken to Cyclophosphamide phosphoramide and acrolein DNA strand breakage DNA strand breakage Melphalan, Pharmacokinetics Parenteral, topical - t1/2 = 7 min. - Cell cycle nonspecific: only seen in actively dividing cells, most susceptible in G1 & S - Resistance: ↓ permeability, ↑ ability to repair, ↑ GSH - Greater stability than Mechlorethamine - Phosphoramide is cytotoxic - Resistance: ↑ metabolism (aldehyde DH) Chlorambucil: slowest A/E, Toxicity, Other Extreme vesicant (if escapes veins), mutagenic, carcinogenic, BM toxicity, acute & delayed nausea, alopecia Not a vesicant, ↓ BM toxicity, ↑ GI toxicity, Hemorrhagic cystitis (acrolein), bladder cancer, SIADH Not a vesicant; no alopecia Chemotherapy: p. 2 of 5 Chlorambucil, Thiotepa, HMM Busulfan Alkylating Agents, suite Drugs Procarbazine [Thiotepa & HMM: release of formaldehyde] BM suppression only - Patients have sense of well being, ↑ appetite Actions Microsomal oxidation to azoprocarbazine & H2O2 cause DNA strand scission + weak MAOI P450 activation to form azoprocarbazine causing RNA strand scission & protein synthesis block Activated in vivo to form organic isocyanates (cause carbamoylation of Lys residues on proteins) & inhibit DNA repair No formation of isocyanates; DNA strand breakage metabolized; ↑ risk of 2° ca. Selective for granulocytes: remission in 80-90% of those with chronic granulocytic leukemia Pharmacokinetics - Crosses BBB - Less acute nausea Thrombocytopenia, hyperuricemia (give with Allopurinol & hydration), nephrotoxicity A/E, Toxicity, Other Severe nausea & vomiting, 2° cancers (leukemia) Contraindications: CNS depressants, MAOI, TCA Mild BM suppression, nausea & vomiting, flu-like syndrome Delayed BM suppression (profound), frequent acute nausea & vomiting; renal toxicity; vesicant Dacarbazine Nitrosureas Carmustine, Lomustine, Semustine - Crosses BBB - Hepatic metabolism - Crosses BBB - Takes 6-8 weeks to recover from BM suppression High affinity for β cells of islets of Langerhans - Indicated for pancreatic carcinomas - Cl & NH3 attached to platinum in cis configuration - ↑↑ Protein bound (90%) - Cell cycle nonspecific - Poor CNS penetration - ↑ Concentration in kidney, liver, GI & testes Carboplatin: ovarian ca. (less bound- less A/E, more BM) Oxoplatin: GI cancers (least A/E) Streptozocin, Chloroxotocin Nausea & vomiting; anemia Cisplatin Bifunctional alkylation after hydrolysis of Cl ions: interand intra-strand cross linkage causing DNA strand break Carboplatin Oxoplatin Marked acute nausea/emesis (within min); distal tubular necrosis, ototoxicity (loss of high frequency), neuropathy, anaphylaxis, moderate myelosuppression - Can reduce toxicity with Cl diuresis or giving NaSCN; also hydration Antimetabolites -- Cell cycle specific: affects S phase - All prodrugs (except MTX) Drugs Actions Folic acid analogue: Methotrexate (MTX) inhibition of DHFR (interferes with 1-C transfers) - Also indirectly inhibits thymidylate synthetase - Net ↓ purine synthesis Pharmacokinetics - IV & p.o. - 35% plasma protein bound - Renal secretion (↑ UV with ↑ pH to prevent precipitation) - Can rescue normal cells with leucovorin (THF) - Resistance: ↑ ic [DHFR], ↓ transport/affinity, ↓ synthesis of polyglutamates, P-gp - Competes with OAT for secretion A/E, Toxicity, Other - Toxic polyglutamates retained in liver/kidney - BM suppression, delayed GI toxicity, alopecia, teratogenic, nephrotoxic & hepatotoxic (no EtOH, annual liver Bx) - Interstitial pneumonitis - Displaces other Rx (phenytoin, Sulfas, ASA, Chemotherapy: p. 3 of 5 tetracyclines) - Prodrug, given IV - Crosses BBB - Leucovorin ↑ efficacy of cytotoxicity - Resistance: ↓ transport, ↑ synthesis of dUMP/enzyme, ↓ affinity, ↓ activation BM suppression, delayed GI toxicities, alopecia, hand & foot syndrome (blistering), acute cerebellar ataxia (rare) - Support with allopurinol 5-Fluorouracil (5-FU) Uracil analogue: inhibition of thymidylate synthetase (activated: 5-FU F-dUMP) Antimetabolites, suite Drugs Actions Cytidine/dCytidine analogue: activated to CTP/dCTP to compete with DNA synthesisDNA synthesis inhibition Sulfur analogues of hypoxanthine & guanine: pseudo-feedback inhibition on HGPRT – blocks de novo purine biosynthesis Nucleotide analogues: adenosine deaminase (ADA) inhibition – inhibits DNA synthesis & repair - Dinucleotide metabolite inhibits ribonucleotide reductase Urea analogue: inhibition of ribonucleoside diphosphate reductase (NT dNT) Pharmacokinetics - Poorly absorbed & rapidly metabolized - Resistance: ↓ kinase, ↓ transport, ↑ deaminase Cytarabine (ara-C) Mercaptopurine (6-MP), Thioguanine (6-TG) - Resistance: ↓ HGPRT, thiopurine dephosphorylation A/E, Toxicity, Other BM suppression, nausea, alopecia - More toxic to granulocytes than lymphocytes (remission in AML) BM suppression, nausea, anorexia, vomiting, hyperuricemia - Give with allopurinol (↓ 6-MP by 75%, no ↓ 6-TG) Dose-limiting BM suppression, prolonged immunosuppression (give TMP-SMX, PCP prophylaxis) BM suppression: megaloblastic anemia, delayed GI toxicity, inflammation & pigmentation if used with radiation Tx Fludarabine, Cladribine, Pentostatin Fludarabine: induces apoptosis - Good for CLL or NHL, Hairy cell leukemia Hydroxyurea - Good p.o. absorption - Renal excretion Natural Products: Vinca Alkaloids -- Cell cycle specific: affects M phase Drugs Actions Pharmacokinetics Vinblastine Bind tubulin to terminate assembly of mitotic spindle: causes “exploded mitosis” - Metabolized by liver: bile excretion - Resistance: ↑ P-gp, tubulin mutation Vincristine Paclitaxel [Taxol] Binds tubulin (at β -site) and promotes assembly: stabilizes & fixates in absence of GTP Topo II inhibition (preventing supercoiling & Resistance: ↑ P-gp, β -site tubulin mutation - Cell cycle specific, but causes S/G2 arrest Etoposide (VP-16), Teniposide (VM-26) A/E, Toxicity, Other Bone marrow suppression, SIADH (hyponatremia) CNS toxicity (paresthesias, loss of reflexes, foot drop, constipation, OH), more alopecia than vinblastine BM suppression, sensory neuropathy - Since different binding site on tubulin, if Vinca resistant, can still use Paclitaxel BM suppression, alopecia, GI toxicity Chemotherapy: p. 4 of 5 allowing for strand breaks) - Resistance: ↑P-gp Antibiotics -- Generally, cell cycle nonspecific (except Bleomycin) - Mechanisms of Action (of Streptomyces strain): bind DNA through intercalation causing steric hindrance; inhibit DNA-dependent RNA synthesis by blocking RNA Pol; ↓ Topo II activity allowing for scission; production of scission by forming free radicals Drugs Actions Binds with guanine bases and causes DNA scission (O2 and Fe2+ radicals) Pharmacokinetics - Cell cycle specific (G2) - Hydrolase degradation (low concentrations in skin & lungs: good for SqC ca., head & neck cancers Pharmacokinetics A/E, Toxicity, Other No major overlap: great for combination chemotherapy - Blistering of the palms, alopecia, pulmonary fibrosis, anaphylaxis - No BM suppression!! A/E, Toxicity, Other Cardiomyopathy, hypotension, tachycardia, CHF, short BM suppression, alopecia, 2° cancers - Daunorubicin: leukemia only, Doxo- broader spectrum ↓ Cardiotoxicity due to ↓ production of free radicals - Severe/total alopecia, short BM suppression - Radiation recall reaction Typical A/E + radiation recall reaction (↑ pigment & inflammation) Bleomycin Antibiotics, suite Drugs Anthracyclines Daunorubicin, Doxorubicin (Adriamycin) Actions DNA intercalation & scission (free radicals from P450), inhibition of Topo II, membrane alteration (ion transport & fluidity) Mitoxantrone Cell cycle nonspecific - Hepatic metabolism - Resistance: ↑ P-gp, ↑ GSH, ↓ Topo II activity - Can give free radical scavengers to ↓ A/E Actinomycin-D DNA intercalation & scission, RNA Pol block, Topo II block Mithramycin (Plicamycin) DNA intercalation & scission interrupts RNA synthesis Reduced by P450 to produce alkylating agent: inhibits DNA synthesis & cross linkages Mitomycin - High potency - Does not cross BBB - Bile & urine excretion - Synergistic with radiation - Highly toxic! (only for very advanced/refractory ca.) - At lower doses: lowers serum Ca2+, used in hypercalcemic patient (effect is unrelated to toxic action) - Very toxic!! - Great for hypoxic tumor - Used with radiation as an adjuvant High toxicity + hypocalcemia, impaired synthesis of clotting factors High toxicity + HUS (due to hemolysis), interstitial pneumonitis, neurological abnormalities Other Chemotherapeutic Agents Drugs Actions Pharmacokinetics Asparaginase Protein synthesis inhibition (blocks required aspartic acid and ammonia) - Isolated from E. coli Stimulation of immune Effective against childhood ALL Biological Response IL-2: Melanoma, RCC A/E, Toxicity, Other Minimal BM toxicity, mucosa & hair follicles - Impaired protein secretion (clotting factors, insulin, albumin, PTH) - Pancreatitis, anaphylaxis Flu-like syndrome, GI Sx Modifiers IL-2, IFN-α -2a, IFN-α -2b Monoclonal Ab Rituximab, Trastuzumab [Herceptin] & many others system to inhibit tumor cell growth (enhances T & NK cells) IFN: Hairy Cell Leukemia, Kaposi sarcoma Chemotherapy: p. 5 of 5 (↓ if pretreat with diuretics), alopecia, BM suppression, nephro-, neuro- & cardiotoxicity (at high doses) Severe hypersensitivity, fever, arrhythmia Expensive! Rituximab: Anti-CD20 Ab Trastuzumab: Anti-EGFR2, HER2-NEU Ab Selective on adrenocortical cells - Indications: inoperable adrenocortical tumor - Support with steroid replacement therapy Liver metabolism Pharmacokinetics - Acute leukemias & lymphomas of childhood - Supportive therapy for hypercalcemia - Improve physical condition (feel better, eat more) Does not effect glucocorticoid or mineralocorticoids Effective on estrogenreceptor + tumors (E+) Unknown Mitotane - Chemically similar to pesticide, DDT Dermatitis, nausea, anorexia, lethargy DNA intercalation & break (Topo II-DNA complex) Steroid Hormones for Cancer Chemotherapy Drugs Actions Amsacrine BM suppression, Cardiac arrest during infusion** A/E, Toxicity, Other Prednisone & other steroids Inhibits lymphocyte mitosis by releasing CKs Hypocalcemia Anastrozole, Letrozole Aromatase inhibitor Estrogen- R antagonist (competition with estradiol) GnRH agonist: initial release of FSH/LH ↓ regulation and desensitization of receptors - Chemical castration: ↓ level of circulating testosterone & estrogen Progestin analogue Estrogen analogue Androgen analogue Fatigue, hot flashes, ↑ risk for osteoporosis Hot flashes, nausea, vomiting, VTE, endometrial ca., osteoporosis Tamoxifen Leuprolide - Prostate cancer - Flutamide (Testosterone-R antagonist) can block flare reaction [initial ↑ in T] Gynecomastia, nausea, emesis, edema, VTE Hydroxyprogesterone caproate, Megesterol Diethylstilbestrol, Ethinyl estradiol Testosterone propionate, Fluoxymesterone Endometrial ca. Antiestrogens have replaced use Prostate & Breast ca. Support with estrogen Na+/H2O retention, CV disorders, hypercalcemia Virilization, hot flashes, ↑ libido, erythrocytosis