Document Detail


Anticancer activity of stabilized palifosfamide in vivo: schedule effects, oral bioavailability, and enhanced activity with docetaxel and doxorubicin.
MedLine Citation:
PMID:  22027537     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Palifosfamide, the DNA-alkylating metabolite of ifosfamide (IFOS), has been synthesized as a stabilized tris or lysine salt and found to have preclinical and clinical antitumor activity. Stabilized palifosfamide overcomes limitations of IFOS because of patient-to-patient variability in response resulting from variable prodrug activation, resistance and toxicities of metabolic byproducts, acrolein and chloroacetaldehyde. Palifosfamide represents an effective alternative to IFOS and other DNA-alkylating prodrugs. The antitumor activities of stabilized palifosfamide were investigated in vivo. Dose response, route and schedule of administration, and interaction with docetaxel or doxorubicin were investigated in NCr-nu/nu mice bearing established orthotopic mammary MX-1 tumor xenografts. Oral activity was investigated in P388-1 leukemia in CD2F1 mice. Oral and intraperitoneal bioavailabilities were compared in Sprague-Dawley rats. Stabilized palifosfamide administered by optimized regimens suppressed MX-1 tumor growth (P<0.05) by greater than 80% with 17% complete antitumor responses and up to three-fold increase in time to three tumor doublings over controls. Median survival in the P388-1 (P<0.001) model was increased by 9 days over controls. Oral bioavailability in rats was 48-73% of parenteral administration, and antitumor activity in mice was equivalent by both routes. Treatment with palifosfamide-tris combined with docetaxel or doxorubicin at optimal regimens resulted in complete tumor regression in 62-75% of mice. These studies support investigation of stabilized palifosfamide in human cancers by parenteral or oral administration as a single agent and in combination with other approved drugs. The potential for clinical translation of the cooperative interaction of palifosfamide-tris with doxorubicin by intravenous administration is supported by results from a recent randomized Phase-II study in unresectable or metastatic soft-tissue sarcoma.
Authors:
Barry Jones; Philip Komarnitsky; Glenn T Miller; John Amedio; Barbara P Wallner
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Anti-cancer drugs     Volume:  23     ISSN:  1473-5741     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2011-12-23     Completed Date:  2012-05-31     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  England    
Other Details:
Languages:  eng     Pagination:  173-84     Citation Subset:  IM    
Affiliation:
ZIOPHARM Oncology Inc., Boston, Massachusetts 02129, USA.
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Animals
Antineoplastic Agents / administration & dosage,  pharmacokinetics,  therapeutic use*
Antineoplastic Combined Chemotherapy Protocols / administration & dosage,  pharmacokinetics,  therapeutic use
Biological Availability
Disease-Free Survival
Dose-Response Relationship, Drug
Doxorubicin / administration & dosage,  therapeutic use*
Drug Administration Schedule
Female
Ifosfamide / administration & dosage,  analogs & derivatives*,  pharmacokinetics,  therapeutic use
Injections, Intravenous
Leukemia, Experimental / drug therapy*
Lysine / administration & dosage,  analogs & derivatives*,  pharmacokinetics,  therapeutic use
Male
Mammary Neoplasms, Experimental / drug therapy*
Mice
Mice, Nude
Phosphoramide Mustards / administration & dosage,  pharmacokinetics,  therapeutic use*
Rats
Rats, Sprague-Dawley
Taxoids / administration & dosage,  therapeutic use*
Xenograft Model Antitumor Assays
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Phosphoramide Mustards; 0/Taxoids; 0/palifosfamide lysine; 15H5577CQD/docetaxel; 23214-92-8/Doxorubicin; 31645-39-3/isophosphamide mustard; 3778-73-2/Ifosfamide; 56-87-1/Lysine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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