JP2017160171A - がん細胞におけるPpIX蓄積増強剤 - Google Patents
がん細胞におけるPpIX蓄積増強剤 Download PDFInfo
- Publication number
- JP2017160171A JP2017160171A JP2016048300A JP2016048300A JP2017160171A JP 2017160171 A JP2017160171 A JP 2017160171A JP 2016048300 A JP2016048300 A JP 2016048300A JP 2016048300 A JP2016048300 A JP 2016048300A JP 2017160171 A JP2017160171 A JP 2017160171A
- Authority
- JP
- Japan
- Prior art keywords
- ppix
- cancer
- group
- accumulation
- cancer cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 114
- 201000011510 cancer Diseases 0.000 title claims abstract description 113
- 238000009825 accumulation Methods 0.000 title claims abstract description 61
- 230000002708 enhancing effect Effects 0.000 title claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 60
- 230000004663 cell proliferation Effects 0.000 claims abstract description 27
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
- 210000004027 cell Anatomy 0.000 claims description 184
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical group C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 claims description 31
- 229940079593 drug Drugs 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 229940123573 Protein synthesis inhibitor Drugs 0.000 claims description 7
- 239000000007 protein synthesis inhibitor Substances 0.000 claims description 7
- 230000022131 cell cycle Effects 0.000 claims description 6
- 239000003534 dna topoisomerase inhibitor Substances 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- 229940044693 topoisomerase inhibitor Drugs 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 229940122815 Aromatase inhibitor Drugs 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 230000000340 anti-metabolite Effects 0.000 claims description 3
- 229940100197 antimetabolite Drugs 0.000 claims description 3
- 239000002256 antimetabolite Substances 0.000 claims description 3
- 239000003972 antineoplastic antibiotic Substances 0.000 claims description 3
- 239000003886 aromatase inhibitor Substances 0.000 claims description 3
- 230000025090 microtubule depolymerization Effects 0.000 claims description 3
- 230000029115 microtubule polymerization Effects 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 229940000425 combination drug Drugs 0.000 claims description 2
- 238000013329 compounding Methods 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- YRMCBQLZVBXOSJ-PCFSSPOYSA-N (e)-3-[(6r,6as)-4-hydroxy-6-methoxy-3-methyl-11-oxo-5,6,6a,7-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]prop-2-enamide Chemical compound CO[C@H]1NC2=C(O)C(C)=CC=C2C(=O)N2C=C(\C=C\C(N)=O)C[C@@H]12 YRMCBQLZVBXOSJ-PCFSSPOYSA-N 0.000 claims 1
- 229940126585 therapeutic drug Drugs 0.000 claims 1
- ZLHFONARZHCSET-UHFFFAOYSA-N 5-aminolevulinic acid hydrochloride Chemical compound Cl.NCC(=O)CCC(O)=O ZLHFONARZHCSET-UHFFFAOYSA-N 0.000 abstract description 24
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 67
- 229950003776 protoporphyrin Drugs 0.000 description 67
- 230000000694 effects Effects 0.000 description 18
- 230000010261 cell growth Effects 0.000 description 17
- 230000003833 cell viability Effects 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 14
- -1 isobutyryl Chemical group 0.000 description 13
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229960000485 methotrexate Drugs 0.000 description 12
- 238000002428 photodynamic therapy Methods 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 11
- QUTFFEUUGHUPQC-ILWYWAAHSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]hexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC1=CC=C([N+]([O-])=O)C2=NON=C12 QUTFFEUUGHUPQC-ILWYWAAHSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000003504 photosensitizing agent Substances 0.000 description 10
- 238000001407 pulse-discharge detection Methods 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 230000003247 decreasing effect Effects 0.000 description 9
- 238000010195 expression analysis Methods 0.000 description 9
- 238000010899 nucleation Methods 0.000 description 9
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 108010078791 Carrier Proteins Proteins 0.000 description 7
- 230000022534 cell killing Effects 0.000 description 7
- 230000005059 dormancy Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 229960002949 fluorouracil Drugs 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 5
- 102100022595 Broad substrate specificity ATP-binding cassette transporter ABCG2 Human genes 0.000 description 5
- 108010090306 Member 2 Subfamily G ATP Binding Cassette Transporter Proteins 0.000 description 5
- 229950004398 broxuridine Drugs 0.000 description 5
- 238000012258 culturing Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- 150000004032 porphyrins Chemical class 0.000 description 5
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 230000001678 irradiating effect Effects 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical class NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 3
- 102100021503 ATP-binding cassette sub-family B member 6 Human genes 0.000 description 3
- 238000009010 Bradford assay Methods 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 101000677883 Homo sapiens ATP-binding cassette sub-family B member 6 Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 108091006594 SLC15A1 Proteins 0.000 description 3
- 102100021491 Solute carrier family 15 member 1 Human genes 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000824 cytostatic agent Substances 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Chemical class 0.000 description 3
- 238000001000 micrograph Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- 230000035519 G0 Phase Effects 0.000 description 2
- 230000010190 G1 phase Effects 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 230000018199 S phase Effects 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 238000012136 culture method Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000012758 nuclear staining Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000002165 photosensitisation Effects 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- GVEBOQDOPLERMC-BGCUHRRXSA-N (3r,4r,5s,6r)-6-(hydroxymethyl)-3-[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]oxane-2,4,5-triol Chemical compound O[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@@H]1NC1=CC=C([N+]([O-])=O)C2=NON=C12 GVEBOQDOPLERMC-BGCUHRRXSA-N 0.000 description 1
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical class CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 241000024188 Andala Species 0.000 description 1
- 208000005440 Basal Cell Neoplasms Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- HNBPGMZUKDCQEE-UWTATZPHSA-N D-alanyl phosphate Chemical compound C[C@@H](N)C(=O)OP(O)(O)=O HNBPGMZUKDCQEE-UWTATZPHSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 206010065713 Gastric Fistula Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010067807 Gingival cancer Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000008081 Intestinal Fistula Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 208000005450 Maxillary Sinus Neoplasms Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 102100027913 Peptidyl-prolyl cis-trans isomerase FKBP1A Human genes 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 206010035610 Pleural Neoplasms Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102000005497 Thymidylate Synthase Human genes 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical class O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 201000004488 maxillary sinus cancer Diseases 0.000 description 1
- 208000019303 maxillary sinus carcinoma Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 201000003437 pleural cancer Diseases 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 206010062261 spinal cord neoplasm Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ALA−PDT又はALA−PDDにおいて、がん細胞へのPpIXの蓄積を高める。
【解決手段】
ALA類および細胞増殖を阻害する薬剤を含むことを特徴とする、がん細胞におけるPpIX蓄積増強用の組み合わせ医薬を提供する。
【選択図】図18
Description
(a)下記式(I)で示される化合物:
又はその塩、および、
(b)細胞増殖を阻害する薬剤、
を含むことを特徴とする、
医薬に関する。
(a)下記式(I)で示される化合物:
又はその塩、を含み、
前記医薬は、
(b)がん細胞において、上記化合物から誘導されるPpIXの蓄積を増強するための、細胞増殖を阻害する薬剤と併用される
ことを特徴とする、医薬に関する。
(b)細胞増殖を阻害する薬剤を含み、
前記医薬は、
(a)下記式(I)で示される化合物:
又はその塩
と併用されることを特徴とする、医薬に関する。
(A)治療上有効量の、下記式(I)で示される化合物を前記がん患者に投与するステップ、
又はその塩、および、
(B)治療上有効量の、細胞増殖を阻害する薬剤を前記がん患者に投与するステップ、
を前記がん患者に適用するステップ、を含む、方法に関する。
5.0×105個のPC−3細胞を35mmのEZSPHERE(商標)に播種し、4日間培養することによってがん細胞スフェロイドを形成した。1つの培養皿に2,300個のスフェロイドが形成され、それらの平均直径は、189±30.1μmであった(図1(a))。細胞の播種数を減らすことで、培養4日後にEZSPHERE(商標)とほぼ同じ細胞数が存在するように調整した2次元培養体と比較すると、スフェロイドの細胞密度の高さが際立った(図1(a))。さらに、スフェロイドの全体像を得るためにHoechstを用いて核染色を行い、共焦点レーザー顕微鏡にてZ軸断面を取得した。形成されたスフェロイドはXY断面においては円状、XZ断面もしくはYZ断面においては緩やかな三日月状であった(図1(b))。このことから、スフェロイドの全体像はお椀型であると示唆された。同様にして、EZSPHER(商標)に播種する細胞数を減らすことにより、最も大きいスフェロイドであるS500に加えてS250、S125の合計3段階の大きさのスフェロイドを形成した(図1(c))。
休眠がん細胞に対する一般的な抗がん剤(DNA合成を阻害する薬剤)の効能を調査するために、シスプラチン(CDDP)および5−フルオロウラシル(5−FU)を用いた。CDDPは2本鎖DNAのグアニン同士を架橋することで、DNA複製を阻害する薬剤である。一方で、5−FUはチミジル酸シンターゼを阻害することでチミジンの合成を抑制し、DNA合成を阻害する薬剤である。2次元培養の異なる細胞密度下において薬剤をそれぞれ72時間添加し、MTT法にて細胞生存率を測定した。全ての濃度のCDDPにおいて、細胞密度依存的に殺細胞効果が低下した(図8(a))。特に、6.25 μMではその差が顕著であった(図8(b)(c))。同様に、5−FU 50μMにおいても細胞密度依存的な殺細胞効果の低下が認められた(図9)。細胞密度が高い環境下では休眠がん細胞の割合も高いと考えられるため、休眠がん細胞に対して一般的な抗がん剤の効果が現れにくいことが明らかとなった。
ALA添加後のPpIX蓄積と休眠性との関係性を検証するために、共焦点レーザー顕微鏡およびHPLCを用いてPpIX蓄積を解析した。ALAを添加する濃度・時間は1mM・24時間とし、がん患者にALAを投与する場合と比較して特異な条件にならないよう配慮した。生細胞内のPpIX蓄積を解析するために正立の共焦点レーザー顕微鏡を用い、観察のための検出プログラムを作成した。作成したプログラムはZ軸に対して0.7μmの厚みで写真を撮影するため、細胞の大きさ(約10μm)と比較しても十分な薄さを確保できた。一般的に共焦点レーザー顕微鏡によるスフェロイドの観察は細胞を有機溶媒で固定してから行うことが多い。しかし、固定を行うと疎水性であるPpIXは細胞外へ流出してしまうため、PpIX蓄積を観察するためには生細胞で行う必要がある。一方で、他の3次元培養法であるマトリゲルなどでは、スフェロイドに対して対物レンズが十分に接近できない。これらのことをふまえ、本研究では3次元培養法としてEZSPHER(商標)を選択し、正立の共焦点レーザー顕微鏡を用いて培養皿の上部から撮影を行うことで、上記の問題を克服した。
休眠がん細胞におけるALA−PDTの殺細胞効果を検証するために、PpIX蓄積後の細胞に赤色光を照射した。アポトーシスを待つために、光照射後はインキュベーターで一晩培養し、MTT法によって細胞生存率を算出した。2次元培養において細胞密度依存的に、細胞生存率が低下した(図12(a))。同様に3次元培養においても、スフェロイドの大きさ依存的に細胞生存率が低下した(図12(b))。これらの結果は、細胞内のPpIX蓄積量が細胞密度依存的に増加したためであると考えられる。以上のことから、休眠がん細胞に対してALA−PDTは特に有効な治療法であると示唆された。
ALA添加後のPpIX蓄積と強い相関がある3つのトランスポーター、PEPT1,ABCB6,ABCG2の発現をタンパク質レベルで解析した。なお、発現解析は細胞にALAを添加せずに行った。2次元培養において、細胞密度依存的にPEPT1およびABCB6の発現は亢進し、ABCG2の発現は低下した(図13(a)(b))。スフェロイドにおいても、細胞密度依存的に上記の傾向が認められた(図14(a)(b))。すなわち、細胞密度が高い休眠がん細胞はALAを取り込みやすく、中間体であるCPgenIIIのミトコンドリアへの輸送も速い一方で、ABCG2によるPpIXの排出は遅いため細胞内のPpIX蓄積が増加したと考えられる(図15)。このことは、休眠性依存的にPpIX蓄積が増加したことやALA−PDT効果が亢進したことと一致する。
これまでの実験結果より、「細胞密度依存的にがん細胞の細胞増殖が抑制され、休眠状態へ移行すること」および「休眠性の高いがん細胞においてはPpIX蓄積が多く、ALA−PDT効果も顕著に現れること」の2つを明らかにした。そこで、細胞密度が低い非休眠がん細胞に対して細胞増殖を抑制した擬似的な休眠状態にすることで、ALA添加後のPpIX蓄積を増加させることができるという仮説を立てた。本仮説を検証するために、PC−3細胞の細胞周期をG0/G1期で止める薬剤として報告されているMethotrexate(MTX)およびCycloheximide(CHX)を用いた。非休眠がん細胞モデルは、2次元培養において細胞密度を低くすることで構築した。
Claims (11)
- がん細胞におけるPpIX蓄積増強用組み合わせ医薬であって、
前記医薬は、順次または同時に適用される、
(a)下記式(I)で示される化合物:
又はその塩、および、
(b)細胞増殖を阻害する薬剤、
を含むことを特徴とする、
医薬。 - 請求項1に記載の組み合わせ医薬であって、
前記細胞増殖を阻害する薬剤は、アルキル化薬、白金製剤、タンパク質合成阻害薬、代謝拮抗薬、トポイソメラーゼ阻害薬、微小管重合阻害剤、微小管脱重合阻害薬、トポイソメラーゼ阻害剤、抗腫瘍性抗生物質、細胞周期を調節する因子に対する分子標的薬、アロマターゼ阻害剤、および、ホルモン剤からなる群から選択される薬剤であることを特徴とする、
組み合わせ医薬。 - 請求項2に記載の組み合わせ医薬であって、
前記タンパク質合成阻害薬が、シクロヘキシミドまたはその誘導体であることを特徴とする、
組み合わせ医薬。 - 請求項1〜3に記載の組み合わせ医薬であって、
前記(b)の適用の後に、前記(a)が適用されることを特徴とする、
組み合わせ医薬。 - 請求項1〜3に記載の組み合わせ医薬であって、
前記組み合わせの態様が、配合剤であることを特徴とする、
組合せ医薬。 - 請求項1〜3に記載の組み合わせ医薬であって、
前記組み合わせの態様が、キットであることを特徴とする、
組合せ医薬。 - 請求項1〜3に記載の組合せ医薬であって、
前記「がん細胞におけるPpIX蓄積増強」が、前記(a)の単独投与の場合のがん細胞におけるPpIXの蓄積に比較して、PpIXの蓄積が増強されている
ことを特徴とする、
組合せ医薬。 - がんに対する光線力学的治療用医薬または光線力学的診断用医薬であって、
前記医薬は、
(a)下記式(I)で示される化合物:
又はその塩、を含み、
前記医薬は、
(b)がん細胞において、上記化合物から誘導されるPpIXの蓄積を増強するための、細胞増殖を阻害する薬剤と併用される
ことを特徴とする、
医薬。 - がん細胞におけるPpIX蓄積増強用医薬であって、
前記医薬は、(b)細胞増殖を阻害する薬剤を含み、
前記医薬は、(a)下記式(I)で示される化合物:
又はその塩
と併用されることを特徴とする、
医薬。 - がん患者のがん細胞においてPpIXの蓄積を増強させる方法であって、
(A)治療上有効量の、下記式(I)で示される化合物を前記がん患者に投与するステップ、
又はその塩、および、
(B)治療上有効量の、細胞増殖を阻害する薬剤を前記がん患者に投与するステップ、
を前記がん患者に適用するステップ、を含む、
方法。 - 請求項10に記載の方法であって、
前記ステップ(B)の後に、前記ステップ(A)が実行される
ことを特徴とする、
方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2016048300A JP6649817B2 (ja) | 2016-03-11 | 2016-03-11 | がん細胞におけるPpIX蓄積増強剤 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2016048300A JP6649817B2 (ja) | 2016-03-11 | 2016-03-11 | がん細胞におけるPpIX蓄積増強剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2017160171A true JP2017160171A (ja) | 2017-09-14 |
JP6649817B2 JP6649817B2 (ja) | 2020-02-19 |
Family
ID=59853868
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016048300A Active JP6649817B2 (ja) | 2016-03-11 | 2016-03-11 | がん細胞におけるPpIX蓄積増強剤 |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP6649817B2 (ja) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011225471A (ja) * | 2010-04-16 | 2011-11-10 | Univ Of Tsukuba | 抗癌剤の効果増強剤 |
JP2012012305A (ja) * | 2010-06-29 | 2012-01-19 | Kanazawa Univ | 抗がん剤の作用増強剤 |
WO2015125732A1 (ja) * | 2014-02-21 | 2015-08-27 | Sbiファーマ株式会社 | 治療抵抗性がんの予防用又は治療用組成物 |
JP2016006121A (ja) * | 2011-10-12 | 2016-01-14 | Sbiファーマ株式会社 | 抗ガン剤の副作用の予防剤及び/又は治療剤 |
-
2016
- 2016-03-11 JP JP2016048300A patent/JP6649817B2/ja active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011225471A (ja) * | 2010-04-16 | 2011-11-10 | Univ Of Tsukuba | 抗癌剤の効果増強剤 |
JP2012012305A (ja) * | 2010-06-29 | 2012-01-19 | Kanazawa Univ | 抗がん剤の作用増強剤 |
JP2016006121A (ja) * | 2011-10-12 | 2016-01-14 | Sbiファーマ株式会社 | 抗ガン剤の副作用の予防剤及び/又は治療剤 |
WO2015125732A1 (ja) * | 2014-02-21 | 2015-08-27 | Sbiファーマ株式会社 | 治療抵抗性がんの予防用又は治療用組成物 |
Non-Patent Citations (2)
Title |
---|
CLIN CANCER RES, 2009, VOL.15(10), P.3333-3343, JPN6019034051, ISSN: 0004107694 * |
日本臨床分子形態学会総会, 2011, VOL.43RD, P.64, JPN6019034052, ISSN: 0004107695 * |
Also Published As
Publication number | Publication date |
---|---|
JP6649817B2 (ja) | 2020-02-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6051283B2 (ja) | 抗ガン剤の副作用の予防剤及び/又は治療剤 | |
JP2018076347A (ja) | 腫瘍免疫誘導用組成物 | |
WO2015125732A1 (ja) | 治療抵抗性がんの予防用又は治療用組成物 | |
US9474770B2 (en) | Prophylactic agent and/or therapeutic agent for sepsis | |
US20220370395A1 (en) | Enhancer of photodynamic effect in ala-pdt or ala-pdd | |
JP2022539074A (ja) | ミトコンドリアの標的化及び癌幹細胞の根絶のためのカルボシアニン化合物 | |
JP6649817B2 (ja) | がん細胞におけるPpIX蓄積増強剤 | |
US20230358726A1 (en) | Non-invasive functional companion assays for oncogene targeted therapy for brain cancer | |
WO2020218562A1 (ja) | 治療抵抗性がんの予防又は治療用の医薬組成物 | |
JP5883889B2 (ja) | 光線力学的診断剤、及び、フォトブリーチング防止剤 | |
JP6417477B2 (ja) | Ala−pdt又はala−pddにおける光線力学的効果の増強剤 | |
JP7307427B2 (ja) | 放射線増感剤 | |
US11827588B2 (en) | Compound, agent and composition for the suppression of cancer growth | |
CN103826645A (zh) | 砷在癌症治疗保护中的用途 | |
JP2011225471A (ja) | 抗癌剤の効果増強剤 | |
JP2019119692A (ja) | 放射線治療用増感剤 | |
JP2011524334A (ja) | 細胞増殖抑制組成物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20181206 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20190828 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190910 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191015 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200106 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200117 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6649817 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |