Linked Life Data

2106164

Source:http://linkedlifedata.com/resource/pubmed/id/2106164

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1 Suppl 3
pubmed:dateCreated
1990-3-21
pubmed:abstractText
In vitro and in vivo studies with N,N',N''-triethylene-thiophosphoramide (thiotepa) alone and in combination with cyclophosphamide (CTX) were carried out using the MCF-7 human breast carcinoma cell line and the EMT6 mouse mammary carcinoma cell line. In vitro, survival curves were essentially linear. The cytotoxicity of thiotepa toward MCF-7 cells was markedly dependent on the presence of oxygen during the period of drug exposure, with a 3-log greater cell kill at 500 mumol with cells that were normally oxygenated compared with hypoxic cells. Incubation of thiotepa with an Aroclor 1254-induced rat liver S-9 homogenate in the presence of a reduced nicotinamide adenine dinucleotide phosphate-regenerating system resulted in an eightfold increase in cytotoxicity toward the MCF-7 cells over a wide range of drug concentrations. The thiotepa metabolite N,N',N''-triethylenephosphoramide (TEPA) was significantly less cytotoxic toward the MCF-7 cells than was thiotepa. Simultaneous and immediately sequential treatments with thiotepa and CTX produced supra-additive cell killing of both cell lines, although the magnitude of the supra-additivity was greater in the MCF-7 cell line than in the EMT6 cell line. These drugs Vppeared to be equally effective as thiol-depleting agents. By DNA alkaline elution, there was a pattern of increasing DNA cross-linking similar to the increasing levels of cytotoxicity of this drug combination as the concentrations of thiotepa increased. In the EMT6 tumor in vivo, the maximally tolerated combination therapy (5 mg/kg x 6, thiotepa, and 100 mg/kg x 3, CTX) produced about 25 days of tumor growth delay, which was not significantly different than expected for additivity of the individual drugs. The survival of EMT6 tumor cells after treatment of the animals with the various single doses of thiotepa and CTX was assayed. Tumor cell killing by thiotepa produced a very steep, linear survival curve through 5 logs with increasing dose. The tumor cell survival cure for CTX to 500 mg/kg had linear tumor cell kill through almost 4 logs. In vivo modeling of quasicontinuous exposure (3 intraperitoneal over 9 hours) versus pulse (single-dose) administration of thiotepa and CTX compared EMT6 tumor cell survival with survival of bone marrow as a representative sensitive normal tissue. With CTX, there was a considerable increase in the therapeutic index (killing of tumor cells/killing of colony forming units-granulocyte macrophage) when the same total dose of drug was administered in multiple injections versus a single injection. For thiotepa, smaller increases in therapeutic index were also observed with the multiple-injection schedule.(ABSTRACT TRUNCATED AT 400 WORDS)
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0093-7754
pubmed:author
pubmed:issnType
Print
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
18-32
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1990
pubmed:articleTitle
Preclinical studies relating to the use of thiotepa in the high-dose setting alone and in combination.
pubmed:affiliation
Dana-Farber Cancer Institute, Boston, MA 02115.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't