Cancer Chemotherapy PDF

# Carcinogenesis Steps ## Mutations: - Activate growth-promoting genes - Inactivate growth-inhibiting genes - Alter apoptosis-regulating genes - Confer immortalization - Inactivate DNA-repair genes ## Expression of altered gene products that allow abnormal cell growth and proliferation ## Cat...

# Carcinogenesis Steps ## Mutations: - Activate growth-promoting genes - Inactivate growth-inhibiting genes - Alter apoptosis-regulating genes - Confer immortalization - Inactivate DNA-repair genes ## Expression of altered gene products that allow abnormal cell growth and proliferation ## Categories of genetic changes: - Protooncogenes activation -> oncogenes - Inactivation of tumor suppressor genes --- # Proliferation: - Growth of transformed cells - Increase in number of transformed cells - Dividing cells progress through cell cycle: DNA synthesis/Mitosis is key events ## CDKs govern progression through phases of cell cycle (G1, G2) - Cyclins, or CDK mutations may lead to neoplastic transformation ## Proliferating cancer cell can have 3 potential fates: - Quiescent: Daughter cell enters resting G0 - Cell can enter G1 and proliferate - Cell death --- # Carcinogenesis - Tumor cells do not proliferate in isolation - Transformed cancer cells secrete a variety of chemical mediators to induce a specialized local environment. (EGF, inhibitors of GF signaling) - Some tumors create protective fibrous connective tissue stroma (palpability of tumor) - Most solid tumors require induction of angiogenesis to deliver nutrients into the center of a tumor (angiogenesis inhibitors) --- # Metastasis: - Capability to invade distant tissues and disseminate (mutations that allow invasion, seeding cavities, spread through lymph or blood vessels, and growth in new environment acquired) - Evolution of differential receptor expression patterns and drug sensitivities during the process of gaining mutations - Primary tumor may respond well to chemotherapy, but metastatic cells may be more de-differentiated and respond poorly (metastatic spread represents a poor prognostic sign) --- # Cancer chemotherapy - general characteristics: - By time of clinical detectability, tumor may contain 10^9 cells, progressed to heterogeneity and developed surrounding stroma - 10% of cells proliferating (and susceptible to anti-cancer drug action) - remaining cells in resting phase may restart proliferating if tumor mass is reduced - Single dose of cytotoxic kills a fixed proportion of cancer cells (not a fixed number) present (1st order process). - Intermittent dosing strategy: - Avoiding unacceptable toxicity to normal cells - Allow bone marrow time to recover - Pulling non-dividing cells out of G0 makes them more susceptible to subsequent chemo cycles --- # Anticancer agents: - Given as frequently as possible to discourage tumor regrowth and maximize dose intensity. ## Necessary to repeat treatments in multiple cycles: - Tumor cell population exceeds 10^9 cells, each cycle kills < 99% cells. - Few medication categories: narrower therapeutic index and greater potential for harmful side effects - Growth Fraction is the ratio of proliferating cells to the total number of cells in the tumor (small, rapidly growing cancer with high growth fraction response favorably to chemotherapy) --- # Challenges of cancer chemotherapy: - Adjusting dose to achieve a therapeutic, non-toxic outcome - Customary to base dose on BSA (dose adjustment based on renal function or PK monitoring can meet specific targets) ## Examples: - Carboplatin thrombocytopenia - direct function of AUC - Target methotrexate concentrations - TDM - Pre-treatment molecular testing for breast cancer - 5-Fu therapy and polymorphisms of drug target genes --- # Anticancer agents - general characteristics: - Inhibit mechanisms involved in cell proliferation - Cancer cells traverse the cell cycle frequently and are more sensitive to interference with DNA synthesis and mitosis. - Toxic to both tumor cells and proliferating normal cells (bone marrow, GI epithelium, hair follicles) - Selectivity: Higher proportion of component cells in malignant tumors undergoing division than normal proliferating tissues. - Most target dividing cells (cells in G0, nutrient-starved cells in the center of large tumor) that are not easily killed. --- # Anticancer agents and cell cycle: - According to sites of action along cellular macromolecule synthetic pathways ## 12. Cell cycle specific/ non-specific drugs ### A. The cell cycle - Synthesis of cellular components required for mitosis - Resting state - Mitotic phase (cell divides) ### B. Cell-cycle specific drugs - Antimetabolites - Bleomycin peptide antibiotics - Vinca alkaloids - Etoposide - Effective for high-growth-fraction malignancies, such as hematologic cancers. ### C. Cell-cycle non-specific drugs - Alkylating agents - Antibiotics - Cisplatin - Nitrosoureas - Effective for both low-growth-fraction malignancies, such as solid tumors, as well as high-growth-fraction malignancies. --- # Cell cycle and cancer chemotherapy: - Sensitivity to chemotherapy highest during rapid cell growth. Tumor cells frequently traverse the cell cycle and are more sensitive to interference with DNA synthesis and mitosis. - Systemic therapy: Use of drugs (chemotherapy, hormonal therapy, or targeted therapy) introduced into the bloodstream. This addresses cancer at any anatomic location. - Systemic therapy is often used in conjunction with modalities that constitute local therapy: - Local therapy: Efficacy confined to the applicable anatomic area. (e.g. radiation therapy, surgery) --- # Cancer chemotherapy - general principles: ## Induction phase - 1st line treatment with a chemoRx drug (curative intent) - Aims to eradicate all detectable cancer cells ## Consolidation phase: - Aims to identify any remaining undetectable cancer cells after remission to prolong overall disease-free time and improve overall survival. ## Intensification: - Identical to consolidation chemotherapy - Utilizes a different drug than induction --- # Cancer chemotherapy - general principles: ## Maintenance chemotherapy - Repeated low-dose treatment to prolong remission. ## Salvage chemotherapy/ Palliative chemotherapy - Non-curative intent: To decrease tumor load and increase life expectancy. - Diagram of chemotherapy phases: | Phase | Duration | |-----------------|------------| | Induction | 4-8 weeks | | Induction 2/ | 5-9 months | | extended | | | Consolidation | 5-9 months | | Interim Maintenance| | | Delayed Intensification| | | Consolidation | | | Maintenance | 2-3 years | --- # Cancer chemotherapy - general principles ## Neoadjuvant chemotherapy: - Given prior to local treatment (e.g., surgery) to shrink the primary tumor (also for cancer with a high risk of micrometastatic disease) ## Adjuvant chemotherapy: - Given after local treatment (radiotherapy/surgery) and can be used when there is little evidence of disease, but a high risk of recurrence ## Combination chemotherapy: - Use different drugs simultaneously (differ in mechanism and side-effects) - Minimizing chances of resistance (drugs can be used at a lower dose and reduce toxicity) --- # Pharmacology of anticancer agents: ## Genome synthesis, stability, and maintenance - Agents directed against DNA replication and cell division - Selectivity against cancer cells that tend to have a higher growth fraction and increased susceptibility to DNA damage in some cases - Narrow therapeutic index ## Signal transduction - With the identification of oncogenes and tumor suppressor genes - Agents targeted more specifically at molecular circuitry responsible for dysregulated proliferation of cancer cells --- # Antineoplastic drug classes: ## Cytotoxic drugs: - Alkylating agents and related compounds - Antimetabolites - Cytotoxic antibiotics - Plant derivatives ## Hormones - Drugs that suppress hormone secretion or antagonize hormone action (genetic or molecular targets) and inhibit growth-promoting signals from endocrine hormones ## Protein kinase inhibitors: - Inhibit receptor tyrosine kinases that transduce growth signals in rapidly dividing cells ## Monoclonal antibodies ## Miscellaneous agents (asparaginase) --- # Antineoplastic drug classes: ## I. DNA damaging agents: - Alter DNA structure to promote apoptosis ## II. DNA synthesis and integrity inhibitors: - Block intermediate DNA synthesis steps ## III. Microtubule function inhibitors: - Interfere with mitotic spindle required for cell division ## IV. Additional class(es): - Hormones - Monoclonal antibodies - Signal transduction inhibitors --- # Alkylating agents: - Electrophilin molecules that are attacked by nucleophilic sites on DNA lead to covalent attachment of an alkyl group to the nucleophilic site (directly modifying DNA structure) ## Major alkylating agent types used in cancer chemotherapy: - Nitrogen mustards (e.g. Cyclophosphamide, ifosfamide) - Ethyleneimines (Busulphan) - Nitrosoureas (Lomustine, Carmustine) - Triazenes (Dacarbazine) - Platinum coordination complexes (Cisplatin) - Azaridines (Thiotepa) --- # Alkylating agents and related compounds - Carbonium ion formation: Highly reactive 6-electron carbon ion in the outer shell, react instantaneously with electron donors (amines, hydroxyl, sulfhydryl groups - main step). ## Alkylation can take place on: - Nitrogen or oxygen atoms of base - Phosphate backbone - DNA-associated protein (N7 and 06 atoms of G bases) - Usually have two strong leaving groups - bis-alkylate- Cross-linking (intrastrand or inter-strand) lead to defective replication through pairing of alkyl-G and T, substitution of AT for GC, excision of G, and chain breakage (DNA strands can break if cell tries to replicate cross-linked DNA during replication). - Principal effect occurs during DNA synthesis (DNA zones unpaired and susceptible to alkylation). - Block at G2 phase of the cell cycle leads to apoptotic cell death. - Diagram of Alkylating agent attaching to DNA: - A graphic of guanine base with an alkyl group attached. - Diagram of the cell cycle: - A graphic of the cell cycle. --- # Alkylating agents - bis-alkylation - Diagram of a live cell with bis-alkylation happening on the DNA to prevent DNA Replication. - Diagram of a dead cell. --- # Alkylating agents - nitrogen mustards: - Diagram showing the mechanism of action. - Formula for (R-N-bischloroethyl) --- # Alkylating agents: - Individual agents vary in reaction speed with nucleophiles - Some are powerful vessicants (high reactivity) and can cause skin/soft tissue damage when leaked outside blood vessels - Highly unstable derivatives (e.g., Mechlorethamine) cannot be administered orally due to rapid alkylation of target molecules - Rapid reactivity is exploited (e.g., infusing directly to the tumor (Thiotepa directly into the bladder to treat superficial bladder cancer). - Less reactive derivatives - (e.g., Chlorambucil; Melphalan) - administered orally; - Cyclophosphamide: Useful derivative (non-reactive oral prodrug that requires CYP450 activation). --- # Cyclophosphamide - Prodrug: Rapidly converted in the liver by P450 mixed oxidases to active metabolites and then metabolized further to inactive compounds - Diagram of CYP3A4 converting cyclophosphamide. - Toxicity to UT epithelium (chemical cystitis) is due to acrolein metabolite --- # Cyclophosphamide - uses: - Broad therapeutic use: - Leukaemia - Breast cancer: Adjuvant chemotherapy - Component of combination regimens for Non Hodgkin’s lymphoma - Ovarian cancers - Solid tumors - Non-cancer use: - Immunosuppressant - Rheumatoid Arthritis - Nephrotic Syndrome --- # Alkylating agents: toxicity - Dose-dependent - 3 cell types preferentially affected: - 1. Rapidly proliferating tissues (bone marrow, GI and GU epithelium, hair follicles) - Myelsuppression, GI distress, and alopecia - 2. Organ-specific toxicity ← low activity of a DNA damage repair pathway in that tissue. - 3. Preferential tissue toxicity (toxic compound accumulation (e.g., acrolein) - 4. Carcinogenicity as a class (†risk of secondary malignancies, especially AML). --- # Cyclophosphamide: - Ample fluid intake recommended during routine use - Vigorous i.v. hydration required during high-dose treatment - Brisk hematuria in a patient receiving daily oral therapy should lead to discontinuation - Refractory bladder haemorrhage may even require cystectomy! --- # Antimetabolites - Nucleobases or nucleosides: Structurally related to normal compounds that exist within the cell, but with an altered chemical group. - Inhibit enzymes involved in nucleotide synthesis and metabolism: Interfere with normal purine or pyrimidine precursors by inhibiting or competing with their synthesis in DNA/RNA synthesis - Exploit metabolic differences between cancer and normal cells - By interfering with: - combination of metabolite with a specific enzyme - combination with a specific enzyme with a specific enzyme - transformation into a metabolically inactive or harmful compound. - Maximal cytotoxic effect is in the S-phase (cell cycle specific) --- # Clinically useful antimetabolites: - a. Folic acid antagonists (Methotrexate) - b. Purine antagonists (6-Mercaptopurine; 5-Fluorouracil) - c. Pyrimidine antagonists (Cytosine Arabinoside) --- # Folate antagonists - Methotrexate: - Folate: Essential for purine nucleotide and thymidylate synthesis: DNA synthesis, cell division. Converted via enzymatic reduction to THF cofactors which provide “C” groups for DNA precursor synthesis - Folate must be reduced to function as a cofactor. Reduction → FH4. This is a 2-step reaction catalyzed by DHFR. It initially converts folate FH2 then to FH4. - FH4: Essential co-factor carrying methyl groups necessary for DUMP → DTMP, which is an essential component for DNA synthesis. - Key metabolic event catalyzed by TS -(Folate antagonists interfere with TS synthesis ### Methotrexate: - Folate analog: It irreversibly inhibits DHFR, which leads to critical shortage of intracellular THF supply, cessation of DNA/RNA synthesis, and arrest of cells in S phase. --- # Antimetabolites: folic acid analogs: - Diagram of folic acid metabolism with Methotrexate blocking the process. - MTX → critical shortage of intracellular THF → accumulation of FH2 glutamate (toxic inhibitory substrate)- inhibition TS # Basis for MTX selective toxicity between normal and cancer cells: - Rapidly-growing cancer cells have an increased requirement for compounds that depend on folate intermediates. They may be more susceptible to apoptosis inducing effects. --- # Methotrexate – uses and toxicity: - ALL, BL; AML, other NHLs - Intrathecal - prophylaxis meningeal leukemia - Choriocarcinoma and related trophoblastic tumors - Cancer of the breast, head and neck, ovaries and bladder - Soft tissue sarcomas - Rheumatoid arthritis, Psoriasis; Crohn’s dx, early stage ectopic pregnancy - MTX is cytotoxic to tissues with high GF ("S" phase). It is generally reversible after therapy discontinuation. - GI mucosa ulceration → hemorrhagic desquamating enteritis - MTX is extremely toxic to the fetus (FA essential for proper differentiation of fetal cells and closure of neural tube) --- # Methotrexate rescue therapy: - Folinic acid: N-5-formyltetrahydrofolate of THF (fully reduced folate coenzyme) - This repletes intracellular THF cofactor pools, as it readily converts to other folic acid derivatives. - Does not require DHFR for conversation. - It can also reactivate DHFR even in the presence of MTX which is used to decrease toxic effects of MTX, broaden the utility of high-dose MTX in inflammation, protect against bone marrow suppression, and protect against mucosal inflammation. - The use of high-dose MTX in cancer chemotherapy has been broadened by the development of folinic acid rescue. - Folinic acid (Leucovorin) is administered several hours after otherwise lethal MTX dose. This selectively kills malignant cells while normal cells are rescued. - Cancer cells have decreased rates for folinic acid transport and are harmed by high MTX doses. - Used in combination with 5-FU to enhance 5-FU effects on TS inhibitors. --- # Inhibitors of pyrimidine synthesis: - 5-Fluorouracil is metabolized to fluorouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP) - Diagram of pyrimidine metabolism with 5-FU blocking the process. - FUMP is incorporated into RNA; fdUMP inhibits thymidylate synthase (both actions lead to cell death) - The binding if fdUMP and methylenetetrahydrofolate (folate cofactor) to TS forms covalently bound complex, which inhibits thymidylate formation from uracil; interfering with DNA synthesis. --- # 5-Fluorouracil: MOA - Diagram of 5-FU MOA - Thymidylate synthase inhibition is the main MOA of 5-FU. - 5-FU inhibits DNA synthesis by interfering with thymidylate biosynthesis. - 5-FU is first converted to FdUMP by the same pathway that converts uracil to dUMP - FdUMP then inhibits TS by forming together with MTHF, a stable covalent enzyme-substrate-cofactor complex. - Toxic effects of 5-FU on cells can be explained by either inhibition of thymidylate synthase by fdUMP or by interfering with RNA processing by FUTP. - Cells deprived of dTMP for a sufficient period of time undergo “Thymineless death”. --- # 5 fluorouracil: - Treatment of a wide variety of cancers: - Breast cancer - Topical treatment of pre-malignant keratoses of the skin - Multiple superficial basal cell carcinomas - 5- FU depletes thymidylate from normal cells as well as cancer cells; therefore, it is highly toxic and must be used with care. - Marked individual PK variability in therapeutic index - Little difference between minimum effective dose and maximum tolerated dose - Efficacy is decreased while used concomitantly with allopurinol. - High toxicity as it depletes thymidylate from cancer as well as normal cells. - Cardiotoxicity (angina symptoms associated with coronary artery spasm): Rarely, arrhythmias/ventricular tachycardia. - CNS effects: Progressively delayed central nervous system degeneration. - Used in combination with folinic acid as first-line therapy for colorectal cancer (5-FU inhibits TS by forming a complex involving fdUMP/MTHF/5-FU; increasing MTHF potentiates 5-FU activity. - Capecitabine: Orally available pro-drug of 5-FU with efficacy similar to IV 5-FU --- # Permetrexed - Folate analogue; similar to endogenous folate and DHFR inhibitor MTX - Transported into cells by the reduced folate carrier and polyglutamated by folylpolyglutamate synthase - Polyglutamated pemetrexed: Potent inhibitor of TS and weak DHFR inhibitor - Used as a single agent in second-line treatment of NSCLC and in combination with cisplatin in the treatment of malignant pleural mesothelioma. - To reduce toxicity to normal cells, patients treated with pemetrexed are also given folic acid and vitamin B12 supplementation. - Cytotoxic effect (as 5FU) due to induction of thymine-less cell death. - FDUMP inhibits TS by binding to the DUMP site, Pemetrexed inhibits TS by binding to MTHF. --- # Purine metabolism inhibitors: - 6-Mercaptopurine - Fludarabine - Pentostatin - Cladribine - Clofarabrine - Nelarabrine - Tioguanine - Diagram showing the structure of: - Azathioprine - 6-Mercaptopurine - 6-Thioguanine - Guanine --- # Purine metabolism inhibitors: - Diagram showing the mechanism of action. --- # 6-Mercaptopurine - 6-Mercaptopurine (6MP) and Azathioprine (AZA) are prodrugs that are nonenzymatically converted to 6MP in tissues. They are inosine analogues that inhibit interconversions among purine nucleotides. - 6-MP and 6-TG are excellent substrates for HGPRT (competes with hypoxanthine and guanine for HGPRT) - converted to TIMP - TIMP inhibits several reactions involving IMP: - conversion of IMP to XMP - conversion of IMP to AMP: - (6-methylthioinosinate (MTIMP) is formed by methylation of TIMP) - Some 6-MP is converted to nucleotide derivatives of 6-thioguanine (6-TG). - By sequential action of: - inosinate (IMP) dehydrogenase - xanthylate (XMP) aminase - This converts TIMP to thioguanylic acid (TGMP). - Diagram showing metabolism of purine and 6-MP. --- # 6-Mercaptopurine - uses and side effects: - ALL treatment (maintenance phase of combination therapy regimen) - Active against normal lymphocytes (Crohn's disease, ulcerative colitis) - as immunosuppressive agent - AZA is a more potent immunosuppressive agent compared with 6MP - Bone marrow suppression - Effectiveness and toxicity of 6MP are both potentiated by allopurinol --- # 6-MP/Allopurinol: - Diagram showing the mechanism of action of 6MP, allopurinol, and the effects on purine metabolism. - Allopurinol is a structural hypoxanthine isomer. - It inhibits xanthine oxidase (enzyme that breaks down 6MP). This prevents oxidation of 6MP into inactive metabolite 6-thiouric acid. - Increased levels of hypoxanthine and xanthine - Lower uric acid levels (uric acid is reduced to prevent tumor lysis syndrome). - Allopurinol + 6-MP increases 6MP toxicity, but use in combination with low dose 6-MP allows reduction of 6-MP dose by ⅔, while increasing therapeutic levels of 6MP. --- # 6 MP - Pharmacogenetics: - Thiopurine S-methyltransferase (TPMT): Inactivation of 6-MP which catalyses methylation of 6-MP to 6-methylmecaptopurine (inactive metabolite). - Methylation prevents 6MP from further conversion into active thioguanine nucleotide (TGN) metabolites. - Genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity. - 6MP toxicity is linked to genetic polymorphisms in TPMT. - People with specific allele variants will require dose adjustments, especially those with homozygous variant genotypes. - Homozygores/heterozygotes may have increased levels of TGN metabolites and a risk of bone marrow suppression. --- # Natural and semi-synthetic products - Vinca alkaloids (vinblastine, vincristine, vinorelbine) - Taxanes (paclitaxel, docetaxel) ## Topoisomerase inhibitors: - Camptothecins (topotecan, irinotecan) - Anthracyclines/Cytotoxic Antibiotics (doxorubicin) - Epipodophyllotoxins (etoposide, teniposide) - Enzymes (L-asparaginase, mitomycin C) --- # Antimitotic plant products: - Naturally occurring plant products have cytotoxic effects: - Vinca alkaloids (Vinblastine, Vincristine, Vindesine) - Taxanes (Paclitaxel, Docetaxel) - Camptothecin analogues (Irinotecan, Topotecan) - Epipodophyllotoxins (Etoposide, Teniposide) --- # Vinca alkaloids: - Periwinkle plant (Catharanthus roseus) - Alkaloids with a dimeric chemical structure: - Indole nucleus (catharanthine) - Dihydroindole nucleus (vindoline) - Joined together. - Diagram showing the structure of: - Vincristine - Vinblastine - Aromatic heteropolyclic compounds --- # Vincristine: - Antitumour effect: Interaction with tubulin - Binds to microtubular proteins - Crystallization of microtubule - Inability to separate chromosomes during metaphase - Apoptosis - Diagram showing the action of Vincristine. - Microtubules depend on dynamic instability for physiologic functioning (drugs that inhibit microtubules are preferentially toxic to M-phase cells). - Vinca alkaloids act by inhibiting tubulin polymerization. - Inhibition of cellular activities involving microtubules: - leucocyte phagocytosis - chemotaxis - axonal transport - Affects all rapidly dividing cell types (very specific administration necessary). --- # Pharmacokinetics: - Vd: Within 15 to 30 minutes of IV administration, >90% distributed from blood into tissue (tightly, but not irreversibly, bound). - Metabolism: Hepatic (CYP3A subfamily). - 75% protein-bound. - Hepatic Elimination: - 80% of injected dose excreted via feces - 10-20% excreted via urine - T1/2: Triphasic serum decay pattern (initial, middle, and terminal half-lives = 5 min, 2.3 hrs, 85 hrs respectively). - Terminal half-life 19 - 155 hours. --- # Vincristine - uses/side effects: - Breast cancer, testicular cancer, neuroblastoma, HL/NHL, mycosis fungoides, histiocytosis, and Kaposi’s sarcoma, melanoma - Delivered by IV infusion - Immunosuppressant (ITP, TTP) - Metabolism ↑ by acetaminophen co-administration - Main side effects: Peripheral neuropathy (progressive, tingling numbness, pain, and hypersensitivity to cold, beginning in hands and feet) - Alopecia (may affect adherence) - Accidental injection via intrathecal administration: Highly dangerous (mortality rate approx. 100%) - Ascending paralysis due to: - massive encephalopathy - spinal nerve demyelination - intractable pain --- # Vinblastine - Highly (>99%) protein-bound - Metabolism mediated by hepatic cytochrome P450 3A isoenzymes. - The major route of excretion: Biliary system. - Half-life: Triphasic: - 35 min - 53 min - 19 hours - Absorption, Vd, and clearance information: Not available --- # Vinblastine – common interactions: - Metabolism of Vinblastine: - ↑ when combined with Acetaminophen - ↓ when combined with Albendazole - Metabolism of Aminophylline: - ↑ when combined with Vinblastine - Metabolism of Amitriptyline: - ↓ when combined with Vinblastine. - Risk or severity of adverse effects increased when combined with allopurinol. - [CYP3A metabolism inhibitors (e.g., grapefruit juice) may ↑ vinblastine concentration]; Herbs which induce CYP3A metabolism may ↓ vinblastine) --- # Taxanes: - Naturally occurring compound [bark of Taxus Spp (Yew)] - Aromatic heteropolycyclic compound - Tetracyclic diterpenoids with structure based either on taxane skeleton, or derivatives. - A graphic of Paclitaxel structure. --- # Taxanes: - Hyper-stabilizes microtubule structure (destroys cell's ability to use its cytoskeleton in a flexible manner). - Inhibits microtubule depolymerization - Binds to β subunit of tubulin (“building block” of microtubules): microtubule/paclitaxel complex does not have the ability to disassemble. - Shortening and lengthening of microtubules (dynamic instability) is necessary for their function as a transportation highway for the cell (e.g., chromosomes rely upon this property of microtubules during mitosis) - Paclitaxel also induces apoptosis by binding to Bcl-2 (B-cell leukaemia 2) apoptosis stopping protein, arresting its function. --- # Paclitaxel - interactions: - Metabolism increased when combined with Acetaminophen - Co-administration with echinacea may decrease effectiveness of immunosuppressants (echinacea may also induce CYP3A4, increasing paclitaxel metabolism) - Grapefruit juice (CYP3A4) ↑ serum paclitaxel concentration) - Herbs (e.g., SJWort) induce CYP3A4 metabolism; may reduce paclitaxel concentration. - Symptoms of overdose: - Bone marrow suppression - Peripheral neurotoxicity - Mucositis - Also been associated with: - Birth defects - Hypersensitivity --- # Camptothecin analogs: - Camptotheca acuminata (Happy tree) - Heterocyclic compounds - Planar pentacyclic ring structure: - That includes a pyrrolo[3,4-beta]-quinoline moiety - Conjugated pyridone moiety - Chiral center within alpha-hydroxy lactone ring with (S) configuration - Diagram showing the structure of a Camptothecin analog. --- # Camptothecin-Topoisomerase I: - (Nuclear enzyme that regulates DNA topology and facilitates DNA replication, recombination, and repair) - Modulates supercoiling by complexing with DNA and nicking one of its two strands. - Camptothecins act by stabilizing this nicked DNA complex preventing topoisomerase I from religating the strand break → apoptosis (Relieves torsional strain in DNA by inducing reversible single-strand breaks, allowing single DNA strands to pass through the break). - Other replicating enzymes then bind to camptothecin-DNA-topoisomerase complex converting single-strand DNA lesion to double-strand break (cancer cells unable to repair resulting damage). --- # Irinotecan: - Hydrophilic prodrug hepatic metabolism (via carboxylesterase) - SN-38: Lipophilic metabolite (>1000-fold topoisomerase I inhibitor than the parent compound) but highly protein-bound and has a shorter half-life - SN-38 is subsequently conjugated by UDP-glucuronosyl transferase 1A1 (UGT1A1) to glucuronide metabolite. - Cmax when a dose of 340 mg/m^2 is to patients with solid tumors is 3392 ng/mL. The AUC (0-24) is 20,604 ng-h/mL. - Vd of terminal elimination phase is 234 L/m^2 (340 mg/m^2 in patients with solid tumors). 30%-68% protein-bound - Half-life: 6 - 12 hours; Terminal elimination half-life of active metabolite, SN-38 = 10 - 20 hours. --- # Irinotecan-uses: - Metastatic carcinoma of colon or rectum - Used in combination with cisplatin for the treatment of small cell lung cancer - In combination with fluorouracil and leucovorin for metastatic adenocarcinoma of the pancreas - Under investigation for metastatic or recurrent cervical cancer - Clinical use is limited by severe GI toxicity (potentially life-threatening diarrhoea) --- # Irinotecan - Interactions: - Metabolism increased when co-administered with Acetaminophen - Dose-dependent bone marrow depression - Risk or severity of adverse effects increased when co-administered with Allopurinol; neutropenia severity increased when co-administered with Amitriptyline - No significant food interactions - Topotecan: Used for metastatic ovarian cancer, SCLC (effective in ovarian cancer resistant to cisplatin) --- # Anthracyclines/cytotoxic antibiotics: - Natural antitumour antibiotics (from fungus Streptomyces) - Among the most clinically useful cytotoxic anticancer agents - Produce their effects through direct action on DNA: - Prevent cell division - Direct action on DNA - Blocking enzymes involved in DNA replication - Both actions (via topoisomerase II) - strand scision/cell death - Doxorubicin (Adriamycin) - Dactinomycin (actinomycin D) - Daunorubicin - Epirubicin - Idarubicin --- # Doxorubicin/Adriamycin: - Aromatic heteropolycyclic compound - Main cytotoxic action mediated via effect on topoisomerase II (Îactivity in proliferating cells) ## Actions: - 1. Intercalates in DNA: - Stabilization of DNA-topoisomerase II complex after strand nicking → prevents DNA re-sealing; halts replication of DNA helix during mitotic segregation. - 2. Induces eviction of histone from transcriptionally active chromatin (→ deregulation of DNA damage response). - 3. Increase free radical (quinone type) production. --- # Doxorubicin-Adriamycin- therapeutic uses: ## Disseminated neoplastic conditions: - Acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin’s disease, malignant lymphoma, and bronchogenic carcinoma in which the small cell histologic type is the most responsive compared to other cell types. - ## Adjuvant therapy: - In women with evidence of axillary lymph node involvement following resection of primary breast cancer --- # Doxorubicin - ADME: - Absorption information is not available - Distributive half-life: 5 minutes (suggests rapid tissue uptake) - Terminal half-life: 20 - 48 hours - Steady state Vd: 809 to 1214 L/m2 - 74-76% bound to plasma protein (extent to binding is independent of plasma concentration up to 1.1 mcg/mL) - Does not cross the blood-brain barrier. --- # Doxorubicin-metabolism: - Capable of undergoing 3 metabolic routes: - One-electron reduction - Two-electron reduction - Deglycosidation - (However, approximately half of the dose is eliminated from the body unchanged) - Two-electron reduction yields doxorubicinol ([secondary alcohol] - this metabolic pathway is considered primary). - One-electron reduction is facilitated by oxidoreductases to form a doxorubicin-semiquinone radical. - Oxidoreductases: Mitochondrial and cystolic NADPH dehydrogenates, xanthine oxidase, and nitric oxide synthases. - Deglycosidation: Minor metabolic pathway (1-2% undergoes this pathway). --- # Doxorubicin-ADME: - Route of elimination: - 40% of the dose appears in bile in 5 days - 5-12% of the drug/metabolites appears in urine during the same time - Metabolism increased when combined with acetaminophen. - Exercise caution with grapefruit products and herbal products. - Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of doxorubicin. --- # Doxorubicin/Adriamycin – uses/adverse effects: - Administered via IV infusion - Extravasation can cause local tissue necrosis ← IV infusion - Cumulative, dose-related cardiac damage (dysrhythmias and heart failure) - Dilated cardiomyopathy → CCF (most dangerous side effect) - Excessive myocardial free radical production - Downregulation of genes for contractile proteins - p53 mediated apoptosis) - Other effects: - Alopecia - Myelosuppression --- # Epipodophyllotoxins: - Etoposide - Teniposide - Natural compounds occurring in mayapple plant (Podophyllum peltatum) - Graphic showing the structure of an Epipodophyllotoxin. - Tetralin lignans in which the benzene moiety of the tetralin skeleton is fused to a 1,3-dioxolane and cyclohexane is fused to butyrolactone (pyrrolidin-2-one). --- # Etoposide: ## Primary mode of action: - Inhibition of topoisomerase II-mediated relegation of double-strand DNA breaks → DNA damage (strand breakage induced by ternary complex [drug-DNA-enzyme]) formation ## Other modes: - Inhibition of mitochondrial function and nucleoside transport - Form complex with