Preclinical oral antitumor activity of BMS-185660, a paclitaxel derivative
A water soluble paclitaxel derivative, BMS-185660, identified previously as having parenteral activity comparable with that of the parent drug, was evaluated for antitumor activity when given orally. Staged subcutaneous (s.c.) tumor models of both murine and human origin were used for this purpose....
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| Veröffentlicht in: | Cancer chemotherapy and pharmacology 2000, Vol.46 (3), p.246-250 |
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| creator | ROSE, W. C LEE, F. Y. F GOLIK, J KADOW, J |
| description | A water soluble paclitaxel derivative, BMS-185660, identified previously as having parenteral activity comparable with that of the parent drug, was evaluated for antitumor activity when given orally.
Staged subcutaneous (s.c.) tumor models of both murine and human origin were used for this purpose.
BMS-185660 achieved levels of activity following oral administration which were comparable with those maximum effects obtained using intravenous (i.v.) paclitaxel. Consecutive daily oral administrations of BMS-185660 resulted in maximum gross log cell kill (LCK) values of 1.7-2.0 in two experiments involving the s.c. Madison 109 murine lung tumor model, which were comparable with the best effects of the derivative injected intravenously, and 0.3 to 0.9 LCK greater than the maximum effects obtained with i.v. paclitaxel; paclitaxel given orally was inactive. Against a human ovarian tumor model with developed resistance to cisplatin (A2780/ cDDP), oral BMS-185660 achieved a maximum LCK of 1.8 compared with i.v. paclitaxel, which produced a maximum 2.4 LCK. Also, in the human HCT-116 colon carcinoma model, oral BMS-185660 cured a maximum of seven of eight mice compared with six of seven mice cured with i.v. paclitaxel. The loss in potency between comparably effective intravenously and orally administered doses of BMS-185660 was about four- to five-fold, but since no drug-associated lethality was ever observed following the oral administration of the highest doses of BMS-185660, further dose escalation may have been tolerated. The intermediate metabolite between BMS-185660 and paclitaxel is BMS-181681. This compound was also evaluated orally and found not to be active versus s.c. M109, despite demonstrating good activity by the i.v. route.
The comparable activities of both intravenously and orally administered BMS-185660 to intravenously administered paclitaxel, combined with the attribute of improved water solubility, provides a good basis for further derivative development. |
| doi_str_mv | 10.1007/s002800000137 |
| format | Article |
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Staged subcutaneous (s.c.) tumor models of both murine and human origin were used for this purpose.
BMS-185660 achieved levels of activity following oral administration which were comparable with those maximum effects obtained using intravenous (i.v.) paclitaxel. Consecutive daily oral administrations of BMS-185660 resulted in maximum gross log cell kill (LCK) values of 1.7-2.0 in two experiments involving the s.c. Madison 109 murine lung tumor model, which were comparable with the best effects of the derivative injected intravenously, and 0.3 to 0.9 LCK greater than the maximum effects obtained with i.v. paclitaxel; paclitaxel given orally was inactive. Against a human ovarian tumor model with developed resistance to cisplatin (A2780/ cDDP), oral BMS-185660 achieved a maximum LCK of 1.8 compared with i.v. paclitaxel, which produced a maximum 2.4 LCK. Also, in the human HCT-116 colon carcinoma model, oral BMS-185660 cured a maximum of seven of eight mice compared with six of seven mice cured with i.v. paclitaxel. The loss in potency between comparably effective intravenously and orally administered doses of BMS-185660 was about four- to five-fold, but since no drug-associated lethality was ever observed following the oral administration of the highest doses of BMS-185660, further dose escalation may have been tolerated. The intermediate metabolite between BMS-185660 and paclitaxel is BMS-181681. This compound was also evaluated orally and found not to be active versus s.c. M109, despite demonstrating good activity by the i.v. route.
The comparable activities of both intravenously and orally administered BMS-185660 to intravenously administered paclitaxel, combined with the attribute of improved water solubility, provides a good basis for further derivative development.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s002800000137</identifier><identifier>PMID: 11021743</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Administration, Oral ; Animals ; Antineoplastic agents ; Antineoplastic Agents, Phytogenic - pharmacology ; Biological and medical sciences ; Chemotherapy ; Colonic Neoplasms - drug therapy ; Drug Screening Assays, Antitumor ; Female ; Humans ; Injections, Intravenous ; Injections, Subcutaneous ; Lung Neoplasms - drug therapy ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Mice, Inbred DBA ; Mice, Nude ; Neoplasm Transplantation ; Ovarian Neoplasms - drug therapy ; Paclitaxel - analogs & derivatives ; Paclitaxel - pharmacology ; Pharmacology. Drug treatments ; Taxoids</subject><ispartof>Cancer chemotherapy and pharmacology, 2000, Vol.46 (3), p.246-250</ispartof><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c318t-f71b19eee1cdc85493c37105d86c12d6733ef1e6740a6b2c1203423744f6a9493</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1495949$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11021743$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ROSE, W. C</creatorcontrib><creatorcontrib>LEE, F. Y. F</creatorcontrib><creatorcontrib>GOLIK, J</creatorcontrib><creatorcontrib>KADOW, J</creatorcontrib><title>Preclinical oral antitumor activity of BMS-185660, a paclitaxel derivative</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><description>A water soluble paclitaxel derivative, BMS-185660, identified previously as having parenteral activity comparable with that of the parent drug, was evaluated for antitumor activity when given orally.
Staged subcutaneous (s.c.) tumor models of both murine and human origin were used for this purpose.
BMS-185660 achieved levels of activity following oral administration which were comparable with those maximum effects obtained using intravenous (i.v.) paclitaxel. Consecutive daily oral administrations of BMS-185660 resulted in maximum gross log cell kill (LCK) values of 1.7-2.0 in two experiments involving the s.c. Madison 109 murine lung tumor model, which were comparable with the best effects of the derivative injected intravenously, and 0.3 to 0.9 LCK greater than the maximum effects obtained with i.v. paclitaxel; paclitaxel given orally was inactive. Against a human ovarian tumor model with developed resistance to cisplatin (A2780/ cDDP), oral BMS-185660 achieved a maximum LCK of 1.8 compared with i.v. paclitaxel, which produced a maximum 2.4 LCK. Also, in the human HCT-116 colon carcinoma model, oral BMS-185660 cured a maximum of seven of eight mice compared with six of seven mice cured with i.v. paclitaxel. The loss in potency between comparably effective intravenously and orally administered doses of BMS-185660 was about four- to five-fold, but since no drug-associated lethality was ever observed following the oral administration of the highest doses of BMS-185660, further dose escalation may have been tolerated. The intermediate metabolite between BMS-185660 and paclitaxel is BMS-181681. This compound was also evaluated orally and found not to be active versus s.c. M109, despite demonstrating good activity by the i.v. route.
The comparable activities of both intravenously and orally administered BMS-185660 to intravenously administered paclitaxel, combined with the attribute of improved water solubility, provides a good basis for further derivative development.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Chemotherapy</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Female</subject><subject>Humans</subject><subject>Injections, Intravenous</subject><subject>Injections, Subcutaneous</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred DBA</subject><subject>Mice, Nude</subject><subject>Neoplasm Transplantation</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Paclitaxel - analogs & derivatives</subject><subject>Paclitaxel - pharmacology</subject><subject>Pharmacology. 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F</creator><creator>GOLIK, J</creator><creator>KADOW, J</creator><general>Springer</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>2000</creationdate><title>Preclinical oral antitumor activity of BMS-185660, a paclitaxel derivative</title><author>ROSE, W. C ; LEE, F. Y. F ; GOLIK, J ; KADOW, J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c318t-f71b19eee1cdc85493c37105d86c12d6733ef1e6740a6b2c1203423744f6a9493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Chemotherapy</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Female</topic><topic>Humans</topic><topic>Injections, Intravenous</topic><topic>Injections, Subcutaneous</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred DBA</topic><topic>Mice, Nude</topic><topic>Neoplasm Transplantation</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Paclitaxel - analogs & derivatives</topic><topic>Paclitaxel - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Taxoids</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>ROSE, W. C</creatorcontrib><creatorcontrib>LEE, F. Y. F</creatorcontrib><creatorcontrib>GOLIK, J</creatorcontrib><creatorcontrib>KADOW, J</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>ROSE, W. C</au><au>LEE, F. Y. F</au><au>GOLIK, J</au><au>KADOW, J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preclinical oral antitumor activity of BMS-185660, a paclitaxel derivative</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2000</date><risdate>2000</risdate><volume>46</volume><issue>3</issue><spage>246</spage><epage>250</epage><pages>246-250</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><abstract>A water soluble paclitaxel derivative, BMS-185660, identified previously as having parenteral activity comparable with that of the parent drug, was evaluated for antitumor activity when given orally.
Staged subcutaneous (s.c.) tumor models of both murine and human origin were used for this purpose.
BMS-185660 achieved levels of activity following oral administration which were comparable with those maximum effects obtained using intravenous (i.v.) paclitaxel. Consecutive daily oral administrations of BMS-185660 resulted in maximum gross log cell kill (LCK) values of 1.7-2.0 in two experiments involving the s.c. Madison 109 murine lung tumor model, which were comparable with the best effects of the derivative injected intravenously, and 0.3 to 0.9 LCK greater than the maximum effects obtained with i.v. paclitaxel; paclitaxel given orally was inactive. Against a human ovarian tumor model with developed resistance to cisplatin (A2780/ cDDP), oral BMS-185660 achieved a maximum LCK of 1.8 compared with i.v. paclitaxel, which produced a maximum 2.4 LCK. Also, in the human HCT-116 colon carcinoma model, oral BMS-185660 cured a maximum of seven of eight mice compared with six of seven mice cured with i.v. paclitaxel. The loss in potency between comparably effective intravenously and orally administered doses of BMS-185660 was about four- to five-fold, but since no drug-associated lethality was ever observed following the oral administration of the highest doses of BMS-185660, further dose escalation may have been tolerated. The intermediate metabolite between BMS-185660 and paclitaxel is BMS-181681. This compound was also evaluated orally and found not to be active versus s.c. M109, despite demonstrating good activity by the i.v. route.
The comparable activities of both intravenously and orally administered BMS-185660 to intravenously administered paclitaxel, combined with the attribute of improved water solubility, provides a good basis for further derivative development.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>11021743</pmid><doi>10.1007/s002800000137</doi><tpages>5</tpages></addata></record> |
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| subjects | Administration, Oral Animals Antineoplastic agents Antineoplastic Agents, Phytogenic - pharmacology Biological and medical sciences Chemotherapy Colonic Neoplasms - drug therapy Drug Screening Assays, Antitumor Female Humans Injections, Intravenous Injections, Subcutaneous Lung Neoplasms - drug therapy Medical sciences Mice Mice, Inbred BALB C Mice, Inbred DBA Mice, Nude Neoplasm Transplantation Ovarian Neoplasms - drug therapy Paclitaxel - analogs & derivatives Paclitaxel - pharmacology Pharmacology. Drug treatments Taxoids |
| title | Preclinical oral antitumor activity of BMS-185660, a paclitaxel derivative |
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