EP0249632A4 - Antitumormittel vom athracyclintyp mit l-ascorbinsäure. - Google Patents
Antitumormittel vom athracyclintyp mit l-ascorbinsäure.Info
- Publication number
- EP0249632A4 EP0249632A4 EP19870900499 EP87900499A EP0249632A4 EP 0249632 A4 EP0249632 A4 EP 0249632A4 EP 19870900499 EP19870900499 EP 19870900499 EP 87900499 A EP87900499 A EP 87900499A EP 0249632 A4 EP0249632 A4 EP 0249632A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- ascorbic acid
- antitumor
- ratio
- antitumor agents
- anthracycline
- 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.)
- Withdrawn
Links
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 title claims abstract description 50
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 28
- 229960005070 ascorbic acid Drugs 0.000 title claims abstract description 23
- 229940045799 anthracyclines and related substance Drugs 0.000 title claims abstract description 22
- 235000000069 L-ascorbic acid Nutrition 0.000 title claims abstract description 20
- 239000002211 L-ascorbic acid Substances 0.000 title claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 230000000259 anti-tumor effect Effects 0.000 claims description 10
- 230000037396 body weight Effects 0.000 claims description 5
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- RKVAWELVULTAKH-UHFFFAOYSA-N CC(O)=O.CC(O)=O.C1=CC=C2C=C(C(=O)C(C(O)=C3O)=O)C3=CC2=C1 Chemical compound CC(O)=O.CC(O)=O.C1=CC=C2C=C(C(=O)C(C(O)=C3O)=O)C3=CC2=C1 RKVAWELVULTAKH-UHFFFAOYSA-N 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 abstract description 7
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 40
- 229960004679 doxorubicin Drugs 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- 241000699670 Mus sp. Species 0.000 description 7
- ZWCKUVMZBKQQRG-UHFFFAOYSA-N 2-[[5,8-dihydroxy-4-[2-(2-hydroxyethylazaniumyl)ethylamino]-9,10-dioxoanthracen-1-yl]amino]ethyl-(2-hydroxyethyl)azanium;diacetate Chemical compound CC([O-])=O.CC([O-])=O.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCC[NH2+]CCO)=CC=C2NCC[NH2+]CCO ZWCKUVMZBKQQRG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 206010003445 Ascites Diseases 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000006820 DNA synthesis Effects 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 102000007999 Nuclear Proteins Human genes 0.000 description 2
- 108010089610 Nuclear Proteins Proteins 0.000 description 2
- 230000006819 RNA synthesis Effects 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- -1 alkali metal salt Chemical class 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- PITHJRRCEANNKJ-UHFFFAOYSA-N Aclacinomycin A Natural products C12=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CCC(=O)C(C)O1 PITHJRRCEANNKJ-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- LWFDUMPGOAKHKC-UHFFFAOYSA-N C1=CC=C2C=C(C(=O)C(C(O)=C3O)=O)C3=CC2=C1 Chemical compound C1=CC=C2C=C(C(=O)C(C(O)=C3O)=O)C3=CC2=C1 LWFDUMPGOAKHKC-UHFFFAOYSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 241000187081 Streptomyces peucetius Species 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 206010006007 bone sarcoma Diseases 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 229930188550 carminomycin Natural products 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- 108091092328 cellular RNA Proteins 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000008791 toxic response Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
Definitions
- This invention relates to novel selected mixtures of anthracycline antitumor agents with L-ascorbic acid and their employment as antitumor agents.
- L-ascorbic acid or Vitamin C is a well known physiologically active agent originally isolated by Szent- Gyorgyi. It has many and well known pharmaceutical activities.
- the anthracyclines are a well known class of antitumor agents that have been employed in the clinical treatment of various tumors in humans since at least 1970.
- the best known of the class is doxorubicin (Andriamycin) . It has a wide spectrum of antitumor activity, such activity encompasing a broad range of solic tumors that prior to its isolation from Streptomyces peucetius caesium had been relatively insensitive to chromatherapy, especially the soft tissue and bone sarcomas and bladder cancer.
- the anthracyclines are further characterized by falling into two classes based on their mode of inhibition of DNA synthesis.
- Type I anthracyclines such as aclacinomycin-A and marcellomycin, inhibit whole cellular RNA synthesis at six-seven fold lower concentrations and nucleolar preribosomal synthesis at 170-1250 fold lower concentrations than those required for inhibition of DNA synthesis.
- Structural differences between type I and type II anthracyclines include the presence of 10-carbomethoxy group and a greater number of sugar residues in the Type II compounds. If the 10-carbomethoxy group is removed, the ability to inhibit nucleolar RNA synthesis is decreased and their is a loss of antitumor activity. Removal of sugar residues can also cause a loss of selectivity of the anthracyclines.
- This invention is concerned with Type I anthracyclines exemplified by doxorubicin, carminomycin and dihydroxy anthracenedione (Mitoxantrone) or its diacetate (DHAQ diacetate) .
- the anthracyclines are unique amongst clinical antitumor agents in that many of them including those presently believed to be the most active, have toxic effects which are dose related.
- the major toxicities are myelosuppression including cardiotoxicity in approximately 60 to 80% of the patients, stomatitis in as many as 80%, nausea and/or vomiting in 20 to 55%, and alopecia in virtually all cases.
- the art has attempted to circumscribe the toxicity of doxorubicin and other anthracyclines by limiting the dose. Such efforts have included coadministration with other chemotherapeutic agents, preparation of homologs, and intermittent administration of the drug. Some degree of success has been achieved with these procedures, but there is room for improvement. The art has sought methods for increasing the efficacy of a particular doses or for making possible the administration of the same or larger doses over longer periods of time without triggering a toxic response.
- SUBSTITUTE SHEET tested combinations of adriamycin, ascorbic acid and dimethyl sulfoxide and concluded that the combinations did not alter the effectiveness of adriamycin.
- anthracycline Type I antitumor agents together with anthracycline Type I antitumor agents are effective to improve the efficacy of the selected antitumor agent provided that the correct amounts of each component of the mixture are selected.
- compositions of this invention not only reduce the toxicity of anthracycline Type I antitumor agents, but also increase the antitumor activity of the therapeutic agent.
- the parts by weight ratio of ascorbic acid to antitumor agent will vary with the selected antitumor agents in the
- compositions of the invention Generally it will vary from about 20:1 to 440:1 in compositions having antitumor activity which is greater than that of the same amount of antitumor agent alone.
- the observation which forms the basis of this selective invention is the recognition that
- the effective ratio of L-ascorbic acid to antitumor agent v depends upon the selected antitumor agent.
- doxorubicin With doxorubicin the ratio for improved activity is about 20:1 to 175:1, the preferred ratio being 85:1 to 90:1.
- DHAQ-diacetate dihydroxy anthracenedione diacetate
- SUBSTITUTE SHEET respective ratios are about 55:1 to 440:1 and 220:1 to 230:1. Below these ratios the desired effect is not achieved. Above these ratios the toxicity of the antitumor agent is unacceptably high even in the presence of L- ascorbic acid.
- P-388 is an ascites tumor administered at a concentration of 1,000,000 cells via the intraperitoneal
- the drugs were given via the NCI's recommended intermittent schedule by I.P. injection of P-388 or L-1210 ascites tumor cells on day zero.
- mice were treated with a mixture of L-ascorbic (200 mM) and doxorubicin.
- the doxorubicin powder was reconstituted in 200 mM of the L-ascorbic acid in 0.85% saline to an equivalent concentration of 10 mg/kg body weight, calculated for 22 gram mice.
- the positive control for P-388 was the known antitumor agent 5-fluorouracil (60 mg/kg) in 200 mM of the acid.
- the doses of doxorubicin were prepared fresh daily.
- L-ascorbic acid in 0.85% saline, doxorubicin in 0.85% saline and 0.85% saline served as further controls.
- L-ascorbic acid can be used in the form of its metal salts, preferably an alkali metal salt such as sodium ascorbate, as will be recognized by those skilled in the art.
- the pH of the mixtures employed in the invention is preferably about 7, but any pH, e.g., 6 to 8, which is neither so high or so low as to be toxic is acceptable.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80492285A | 1985-12-05 | 1985-12-05 | |
| US93677086A | 1986-12-02 | 1986-12-02 | |
| US804922 | 1991-12-11 | ||
| US936770 | 1992-08-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0249632A1 EP0249632A1 (de) | 1987-12-23 |
| EP0249632A4 true EP0249632A4 (de) | 1988-06-20 |
Family
ID=27122739
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19870900499 Withdrawn EP0249632A4 (de) | 1985-12-05 | 1986-12-05 | Antitumormittel vom athracyclintyp mit l-ascorbinsäure. |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0249632A4 (de) |
| AU (1) | AU6846687A (de) |
| WO (1) | WO1987003481A1 (de) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1799588A (en) * | 1987-05-11 | 1988-12-06 | Procyte Corporation | Method of tumor inhibition in warm-blooded animals |
| GB2208798B (en) * | 1987-07-20 | 1991-06-05 | Norsk Hydro As | Anti-cancer agent comprising l-ascorbic acid and o-benzylidene-l-ascorbic acid or deuterated derivative |
| GB2224649B (en) * | 1988-11-10 | 1992-08-26 | Charles Lwanga Ssali | Antiviral compositions comprising fusidic acid and l-ascorbic acid |
| US6468980B1 (en) * | 2000-09-01 | 2002-10-22 | Oxycal Laboratories, Inc. | Methods and compositions for potentiating cancer chemotherapeutic agents |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4278689A (en) * | 1978-07-11 | 1981-07-14 | American Cyanamid Company | 1,4-Bis(substituted-amino)-5,8-dihydroxy-anthraquinones and leuco bases thereof |
| ATE48942T1 (de) * | 1984-02-27 | 1990-01-15 | American Cyanamid Co | Verwendung von 1,4 bisubstituierten anthrachinonen zur herstellung von immunsuppressiva. |
-
1986
- 1986-12-05 EP EP19870900499 patent/EP0249632A4/de not_active Withdrawn
- 1986-12-05 AU AU68466/87A patent/AU6846687A/en not_active Abandoned
- 1986-12-05 WO PCT/US1986/002646 patent/WO1987003481A1/en not_active Ceased
Non-Patent Citations (2)
| Title |
|---|
| No relevant documents have been disclosed. * |
| See also references of WO8703481A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1987003481A1 (en) | 1987-06-18 |
| EP0249632A1 (de) | 1987-12-23 |
| AU6846687A (en) | 1987-06-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19870904 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
|
| A4 | Supplementary search report drawn up and despatched |
Effective date: 19880620 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 19880906 |
|
| RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: VELTRI, ROBERT, W. |