Anticancer drugs 醫學系 吳文彬 老師
Outline of this lecture Introduction to cancer General concept of anti-cancer drugs Chemotherapy: CCS drugs Chemotherapy: CCNS drugs Targeted therapy and New drugs Quiz
癌症連續蟬聯 國人十大死因之首
癌症時鐘快 轉! 每5 分40秒就 有1人罹癌 國人十大癌 症出爐大腸 癌蟬聯六度 冠軍 每 251人1人 罹癌 男性 發生率是女 性的 1.3倍 2014/4/15
Diagnosis (?)
Hallmarks of Cancer
Cell. 2000 Jan 7;100(1):57-70.
Treatment Surgery and/or radiation Chemotherapy Immunotherapy Targeted therapy
Immunotherapy?
Adjuvant chemotherapy
Basic and Clinical Pharmacology, 12th Ed., 2012
Overview of anticancer drugs
Adverse effects of chemotherapy
Thrombocytopenia: recombinant IL-11 (oprelvekin, Neumega®) Platelet transfusion Neutro (Leuko)penia: GCSF (granulocyte colony-stimulating factor) (Filgrastim®) and Sargramostim (GM-CSF) Effects on the GI tract and bone marrow are often dose-limiting adverse effects Dose-limiting: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment.
Pharmacology and the Nursing Process, 7e, 2014
CCS drugs: Antimetabolites, natural products and others
Antimetabolites Antifolates: Methotrexate (MTX)
Pharmacological properties
Pharmacological properties
Clinical uses (1)
Clinical uses (2) •
•
•
MTX is administered by the intravenous, intrathecal, or oral route. Renal excretion is the main route of elimination and is mediated by glomerular filtration and tubular secretion. As a result, dose modification is required in the setting of renal dysfunction. Care must also be taken when MTX is used in the presence of drugs such as aspirin, NSAIDs, penicillin, and cephalosporins, as these agents inhibit the renal excretion of MTX. Leucovorin (a rescue drug and antidote) for MTX
Adverse effects and contraindications Adverse effects
Myelosuppression Mucositis Diarrhea Contraindications
Teratogenic Combined with misoprostol (PGE1 analog) to induce early abortion
Antimetabolites Fluoropyrimidines: 5-Fluorouracil (5-FU)
Mechanism of action •
5-FU is inactive in its parent form. One of its metabolites is 5-fluoro-2′-deoxyuridine-5′monophosphate (FdUMP), forming a covalently bound ternary complex with the enzyme TS. This results in inhibition of DNA synthesis through “thymineless death.”
•
5-FU is converted to 5-fluorouridine-5′triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation.
•
5-FU is also converted to 5fluorodeoxyuridine-5′-triphosphate (FdUTP), which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function.
Therapeutic uses ‧ 廣泛性抗癌藥,對光過敏,腸胃道癌症之首選用藥 FOLFOX® (5-FU + Oxaliplatin + Leucovorin) GI toxicity↑(ulceration) → IV administration Because of its extremely short half-life by IV administration, on the order of 10~15 minutes, infusional schedules of administration have been generally favored over bolus schedules. AE: 色素沈積, nausea, diarrhea, neurotoxicity and bone marrow suppression . 手足症候群 (hand-foot syndrome) 在臨床上亦稱為肢 端紅腫症(palmar plantar erythrodysesthesia (PPE))。是一種藥物引 起的皮膚毒性反應,發生在手掌或腳掌,會有泛紅、腫脹及發麻、刺 痛等感覺異常。
Antimetabolites Deoxycytidine analogs: Cytarabine and Gemcitabine
Cytarabine (ara-C) is an S phase-specific antimetabolite that is converted by deoxycytidine kinase to the 5‘mononucleotide (ara-CMP) and then ara-CTP. Ara-CTP competitively inhibits DNA polymerase, thereby resulting in blockade of DNA synthesis and DNA repair, respectively. This metabolite is also incorporated into RNA and DNA. Incorporation into DNA leads to interference with chain elongation and defective ligation of fragments of newly synthesized DNA.
Inhibits ribonucleotide reductase (for dCTP synthesis) Cytarabine syndrome: fever, muscle and bone pain…
Bleomycin
A mixture of different metal chelating glycopeptide
MOA: scission of DNA
Causes accumulation of cells in the G 2 phase of the cell cycle.
Therapeutic uses: Hodgkin’s and non-Hodgkin’s lymphoma, germ cell tumor and head and neck cancer
Toxicity: 1. 掉髮(1-10%)、皮疹(8%)、紅斑(50%)、皮膚色素 過度沉著(50%)、手及指甲角質化(50%)、allergic rx, fever, chills, and hypotension (acute) 2. Pulmonary fibrosis (delayed) (Bleomycin lung)
Natural products 長春花
Tubulin-binding Agents Vinca alkaloids
Vinca alkaloids 之臨床使用
Vincristine and Vinblastine Both are metabolized by cytochrome P-450 Despite their similarities, they have a strikingly different spectrum of clinical activity and safety profile. Vincristine (VX,氧化青春花鹼;Oncovin) 1. ALL (in children)…. 2.周邊神經毒性、有便秘之副作用 (paralytic ileus), myelosuppression ↓ Vinblastine (VBL,長春花鹼) 1. Nausea and vomiting, myelosuppression
Paclitaxel (Taxol®)
Clinical uses and adverse effects of paclitaxel
Paclitaxel (semisynthetic) and docetaxel
Clinical uses: 1. Advanced ovarian cancer and metastatic breast cancer 2. (Non)-Small-cell lung cancer, prostate, bladder cancer, head and neck cancer
Adverse effects
Castor oil : Cremophor EL
Acute- Nausea and vomiting, hypotension, hypersensitivity (due to its oil solvent, premedicated with a steroid, H1 and H2 antagonists) albumin-bound paclitaxel (can interact with gp60) Delayed- myelosuppression and peripheral sensory neuropathy Neutropenia -> GCSF (filgrastim)
Epipodophyllotoxin: Etoposide
八角蓮屬 podophyllum 家族, 含有 epipodophyllotoxin (鬼臼子毒素)
Etoposide (VP-16) Topoisomerase-active Drugs
Clinical uses: • Oral and IV form • IV form (in a hydroalcoholic diluent -> hypotension): can be improved by water-soluble form. 1. Lung cancer 2. Non-Hodgkin’s lymphoma 3. Gem cell tumor 4. Gastric cancer PEB: Cisplatin, etoposide, and bleomycin Adverse effects: Acute nausea and vomiting, hypotension
CCNS drugs: Alkylating agents and antibiotics
Characteristics of Alkylating Agents
Alkylation of DNA damage of DNA Have a broad spectrum of anti-tumor activity and immunosuppression Active against proliferating and nonproliferating cells Cause dose-limiting myelosuppression Pulmonary fibrosis Cytotoxic, mutagenic and carcinogenic (e.g. Procarbazine) lead to a secondary malignancy such as leukemia (leukemogenic effect)
Structures of major classes of alkylating agents
Alkylating Agents
Mechanism of action of alkylating agents
MOA: cell-cycle nonspecific 1. Alkylation 2. Depurination 3. Miscoding mutation
Mechlorethamine
Prototype, but the use of this drug has declined recently Therapeutic uses used primarily in the treatment of Hodgkin’s and non-Hodgkin’s lymphoma MOPP: Mechlorethamine + Oncovin (vincristine) + Prednisone + Procarbazine Adverse effects: nausea and vomiting extravasation → infiltrated with isotonic sodium thiosulfate (1/6 M)
Cyclophosphamide (Endoxan®) Cyclophosphamide (Endoxan®)
廣泛性抗癌,對 (non-)Hodgkin’s lymphoma、CLL、 neuroblastoma、乳房、卵巢及肺癌 Used as an immunosuppressant 有 alopecia、出血性膀胱炎 (導致膀胱纖維化) 之副作用 需監測是否有血尿或排尿困難
Prevented by coadministration of the sulfhydrylreleasing agent (Mesna)
Chlorambucil: CLL and non-Hodgkin’s lymphoma
Melphalan (PAM):Multiple myeloma, breast cancer,
ovarian cancer
烷基化藥物 (Alkylating agents) 亞脂酸尿素 (Nitrosoureas) Carmustine (BCNU) and Lomustine (CCNU):
脂溶性高,故可通過 BBB 以治療腦瘤 (Temozolomide for gliomas and astrocytomas) Busulfan:治療 CML,有肺纖維化、skin
pigmentation and adrenal insufficiency 之副作用 Thiotepa (Tespamine):治療 breast, ovarian
and superficial bladder cancer、膀胱上皮乳頭狀 瘤之用藥
Degradation of carmustine (BCNU) with generation of alkylating and carbamoylating intermediates
Nonclassic alkylating agents: Temozolomide and Dacarbazine
Temozolomide, a triazene agent, has been approved for use against glioblastomas and anaplastic astrocytomas. It is also used in metastatic melanoma.
Dacarbazine is an alkylating agent that must undergo biotransformation to an active metabolite. Similar to other alkylating agents, the cytotoxic action of dacarbazine has been attributed to the ability of its metabolite to methylate DNA on the O6 position of guanine. Dacarbazine has found use in the treatment of melanoma and Hodgkin lymphoma.
Platinum compounds
Cisplatin , Carboplatin and Oxaliplatin MOA: similar to that of the alkylating agents Clinical uses: Non-small and small lung cell cancer, breast, bladder cancer, head and neck cancer, 卵巢癌 (combined with cyclophosphamide), germ cell cancer (PEB) and testicular cancer (cisplatin and etoposide) Oxaliplatin: shows excellent activity against advanced colorectal cancer. Adverse effects:
Anthracyclines: Doxorubicin, daunorubicin, , epirubicin and idarubicin
(Adriamycin®)
Mechanism of action of ~rubicins (1) Inhibition of topoisomerase II (2) High-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand scission (3) Generation of semiquinone free radicals and oxygen free radicals through an irondependent, enzyme-mediated reductive process (4) Binding to cellular membranes to alter fluidity and ion transport
Therapeutic uses • Doxorubicin: for the treatment of sarcoma, carcinoma (breast and lung), Hodgkin’s and non-Hodgkin’s lymphoma, thyroid cancer • Daunorubicin: for acute lymphocytic and myelocytic leukemias (AML & ALL) Toxicity: Stomatitis, nausea and red urine (acute) Cardiac damage (Heart failure and dysrhythmias) (delayed toxicity) liposomal-encapsulated doxorubicin (toxicity and duration ) for ovarian cancer and with bortezomib for multiple myeloma
L-Asparaginase (Elspar®)
Pegaspargase: pegylated asparaginase
L-Asparaginase: MOA: 使癌細胞所需的 L-Asparagine 迅速被 Asparaginase 分解成 Aspartic acid,故無法利用而死亡 Adverse effects: 1. From E. coli: hypersensitivity → fever, chills, nausea and vomiting 2. Severe: bronchospasm, respiratory failure and hypotension 3. 胰臟炎、肝毒性及低纖維蛋白原血症 治療:Acute lymphocytic leukemia
Steroid hormones and their antagonists
Prednisone Lympholytic effects Suppresses mitosis in lymphocytes Therapeutic uses: in pt’ with acute lymphocytic leukemia, (non-) Hodgkin’s lymphomas
Cancer cell resistance 1. Mutations in the p53 tumor suppressor gene. 2. Defects in the mismatch repair enzymes. 3. Multidrug resistance (MDR1) due to ATPdependent pumping of drugs out of the cell in the presence of Pglycoprotein
used in the first-line treatment of Hodgkin lymphoma
New drugs and targets: Targeted therapy
Promotion of tumor growth by Neovascularization (Angiogenesis)
N Engl J Med 333: 1757-1763, 1995
Strategy 1: angiogenesis as a therapeutic target
Strategy 2: Tumor markers as a therapeutic target 1. Target specific tumor (surface) marker 2. Target growth factor signaling pathways
DRUGS TARGETING ANGIOGENESIS
Antiangiogenesis agent Bevacizumab (Avastin®) (癌思停®) Anti-VEGF-A monoclonal Ab A first-line drug against metastatic colorectal cancer Infused Intravenously Adverse effects:
Hypertension, stomatitis (口腔炎), diarrhea. Other drugs: Ziv-aflibercept, Sorafenib, Sunitinib, & Pazopanib
DRUGS TARGETING TUMOR MARKERS
Protein kinase inhibitors
Gefitinib
Gefitinib (Iressa®) and erlotinib (Tarceva®) Gefitinib (Iressa)
1. Small molecule that target the EGF receptor 3. For the treatment of non-small cell lung cancer 4. Adverse effect: 腹瀉(48%)、皮疹(43%) 及interstitial lung disease (rare but fetal) Erlotinib (Tarceva)
Adverse effect: 腹瀉、皮膚紅疹、結膜炎、嘔吐、口腔炎 近年來國家衛生研究院研究發現,所研究之國內肺癌病人組織之表皮生長因子 受體基因之序列分析,發現高達39%的腫瘤具有表皮生長因子受體之突變,其 中以肺腺癌之突變率高達55%,且突變之種類也特別複雜,和西方人顯著不同 (2-11%, 2-5個突變種類),故可能是日本及台灣使用gefitinib超過30%反應率的 原因,而歐美(白種人)只有10%。目前的資料顯示erlotinib對於所有的病患並非 都有同樣的療效
Tyrosine Kinase Inhibitors : Imatinib (Glivec®), Dasatinib, and Nilotinib A tyrosine kinase inhibitor Occupy the “kinase pocket” Orally active Clinical uses:
1. Used as a first-line drug for CML 2. GI stromal tumor Adverse effects: GI distress, fluid retention, edema, thrombocytopenia, neutropenia and potential drug interaction [(-)P450] Other drugs: 1. Dasatinib (binds to the active and inactive conformations of the Abl kinase domain 2. Nilotinib (2nd generation, 20~50 fold than imatinib)
Mechanism of action of ~tinibs
December 15, 2008; Blood: 112 (13). Translation of the Philadelphia chromosome into therapy for CML
Tratuzumab (Herceptin®) HER2 (human epidermal growth factor receptor 2) is
seen in 25-30% of patients. A recombinant DNA-produced, humanized monoclonal Ab, targeting the extracellular domain of the HER2 growth receptor. Used in patient with metastatic breast cancer. Adverse effect: Congestive heart failure (CHF) Cetuximab and Panitumumab
(Abs targeting EGFR): for metastatic colorectal cancer
Rituximab (Mabthera®) A chimeric mAb directed against the CD20 antigen on
B lymphocytes. MOA: complement and Ab-dependent, cell-mediated
cytotoxicity of the B cells. For lymphoma and chronic lymphocytic leukemia
[combined with CH(E)OP] Pharmacokinetics: IV infusion Adverse effects: severe and fatal
Hypotension, bronchospasm, angioedema, chills and fever. Tumor lysis syndrome renal failure.
B cell maturation
Edwards et al. Nature Reviews Immunology 6, 394–403 (May 2006) | doi:10.1038/nri1838
Radioimmunoconjugates •
Radioimmunoconjugates provide targeted delivery of radionuclides to tumor cells. 131Iodine (131I) is a favored radioisotope because it is readily available, relatively inexpensive, and easily conjugated to a monoclonal antibody. The γ particles emitted by 131I can be used for both imaging and therapy, but protein-iodine conjugates have the drawback of releasing free 131I and 131Ityrosine into the blood, and thus present a health hazard to caregivers, family, and others in contact with the patient.
•
The 90Y-emitter has emerged as an attractive alternative to 131I, based on its higher energy and longer path length. These features suggest that it may be more effective in tumors with larger diameters. It also has a short t1/2 and remains conjugated, even after endocytosis, providing a safer profile for outpatient use.
Other Targeted And Miscellaneous Drugs (1)
Proteasome inhibitors Bortezomib was first approved for use in relapsing or refractory multiple myeloma and is now widely used as first-line therapy. This agent is thought to exert its main cytotoxic effects through inhibition of the 26S proteosome, resulting in downregulation of the nuclear factor kappa B (NF-κB) signaling pathway, which is felt to be a major signaling pathway for this disease. Of note, inhibition of NF- κB has also been shown to restore chemosensitivity. Based on this mechanism of action, further efforts have focused on developing bortezomib in various combination regimens.
Nature Reviews Drug Discovery 8, 33-40 (January 2009)
Thalidomide and Lenalidomide
(Dermatology Online Journal, 2009, 15(6): 15
Thalidomide has been reintroduced to clinical practice as an oral agent for the management of erythema nodosum leprosum (ENL) and in other disease settings, most notably Multiple myeloma. Lenalidomide (REVLIMID) is approved for treatment of transfusion-dependent anemia due to low- or intermediate-risk myelodysplastic syndromes associated with the 5q cytogenetic deletion, with or without additional cytogenetic abnormalities. Adverse effect: peripheral neuropathy
Thalidomide catastrophe
Other Targeted And Miscellaneous Drugs (2): Supplementary slides
(For cutaneous Tcell lymphoma)
(For renal cancer)
Histone deacetylase Inhibitors Epigenetic processes are implicated in cancer causation and progression. The acetylation status of histones regulates access of transcription factors to DNA and influences levels of gene expression. Histone deacetylase (HDAC) activity diminishes acetylation of histones, causing compaction of the DNA/histone complex. HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression.
Nature Reviews Drug Discovery 1, 287-299 (April 2002)
mTOR inhibitors •
Rapamycin (sirolimus) is a fungal fermentation product that inhibits the proper functioning of a serine/threonine protein kinase in mammalian cells eponymously named mammalian target of rapamycin, or mTOR, an effector PI3 kinase signaling. The PI3K/PKB(Akt)/ mTOR pathway responds to a variety of signals from growth factors (e.g., insulin, interleukins, EGF) that modulate cell growth, translation, metabolism, and apoptosis.
Questions 1. 下列何者為太平洋紫杉醇(taxol)之衍生物,可用於治療卵巢癌及轉移性乳癌?(A) vincristine (B) paclitaxel (C) doxorubicin (D) dactinomycin。 2. 下列何種抗癌藥比較不會有骨髓抑制的副作用?(A) vinblastine (B) doxorubicin (C) cyclophosphamide (D)bleomycin。 3. 何種抗癌藥會產生嚴重的心臟毒性?(A) doxorubicin (B) bleomycin (C) paclitaxel (D) vincristine。 4. 下列何種藥物之結構為葉酸類似物(folic acid analog),並可有效治療子宮絨毛膜癌? (A) fluorouracil(5-FU) (B) cyclophosphamide (C) vincristine (D) methotrexate。 5. 使用methotrexate作為抗癌藥物時,應與下列何種藥物併用以降低其副作用?(A) leucovorin (B) glucose (C) vitamin B (D) vitamin C。 6. 下列哪一個抗癌藥物作用機轉為抑制DNA合成而作用於細胞週期之S phase?(A) cyclophosphamide (B) ara-C (C) paclitaxel (D) cisplatin。 7. 何種抗癌藥物烴化劑須經肝臟活化後,才可產生烴化作用,且可能造成出血性膀胱炎? (A) mechlorethamine (B) chlorambucil (C) busulfan (D) cyclophosphamide。 8. 有關抗癌藥與其副作用之配對,下列何者錯誤?(A) 5-fluoro-uracil的副作用主要為噁心 、嘔吐和骨髓抑制 (B) cyclophosphamide可能產生出血性膀胱炎 (C) bleomycin會引 起病人肺部纖維化 (D) methotrexate會將病人體液染紅。 9. 下列何種抗癌藥物屬抗代謝藥物,對細胞週期S期具專一性?(A) cyclophosphamide (B) bleomycin (C) vincristine (D) 5-fluorouracil。 10. 有關抗癌藥topotecan的敘述,下列何者錯誤?(A) 主要作用為抑制葉酸的合成 (B) 用於 治療轉移性卵巢癌 (C) 可與cisplatin、paclitaxel合併使用 (D) 副作用包括腹瀉、噁心 、嘔吐等。
Questions 1. 人類重組interleukin-11 又稱為oprelvekin,此生物性製劑主要使用於緩解化療( chemotherapy)引發之何種症狀?(A)Vomiting (B)Severe thrombocytopenia (C)Alopecia(D)Diarrhea 2. 癌症細胞常有過度分裂繁殖之現象。治療癌症之藥物也常針對此特性。下列何種藥物可 以抑制thymidylate synthase?(A)methotrexate (B)5-FU(5-fluorouracil) (C)cyclophosphamide (D)vinca alkaloids(vincristine) 3. 癌細胞對vincristine 與methotrexate 產生抗藥性的原因是增加:(A)黏著分子的表現 (B)DNA repair 酵素的表現 (C)P-glycoprotein transporter 的表現 (D)Glucose-6phosphate dehydrogenase 的表現 4. 下列何種治療乳癌藥物中,對女性乳癌具有專一性的作用? (A)Doxorubicin (B)Trastuzumab (C) Anastrozole (D)Fluoxymesterone 5. 下列何者是5-fluorouracil 的抗癌作用機轉? (A)與DNA 結合而抑制DNA 複製的功能 (B)抑制dihydrofolic acid 還原酵素(C)其代謝物抑制thymidylate synthase 而毒殺細胞 (D)選擇性的抑制DNA polymerase 6. 下列何種抗癌藥物之組合對Hodgkin‘s disease有不錯之療效﹖ (A)ABVD(adriamycin, bleomycin, vinblastine, dacarbazine) (B)CMF(cyclophosphamide, methotrexate, 5fluorouracil) (C)PVC(procarbazine, vincristine, CCNU) (D)BEP(bleomycin, etoposide, cisplatin) 7. 下列之抗癌藥物的作用機制為抑制TopoisomeraseΙΙ,何者為例外? (A)Doxorubicin (B)Mitomycin C (C)Etoposide (D)Daunorubicin 8. 急性前髓細胞白血病 (acute promyelocytic leukemia) 可以用何種藥物,使腫瘤細胞分化 ? (A)Adriamycin (B)Retinoic acid (C)Cyclophosphamide (D)Folic acid