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Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo.

Gullbo, Joachim, (författare)
Uppsala universitet, Institutionen för medicinska vetenskaper, Cancer Pharmacology and Informatics
Lindhagen, Elin, (författare)
Uppsala universitet, Institutionen för medicinska vetenskaper, Cancer Pharmacology and Informatics
Bashir-Hassan, Saadia, (författare)
Uppsala universitet, Institutionen för medicinska vetenskaper, Cancer Pharmacology and Informatics
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Tullberg, Marcus (författare)
Ehrsson, Hans (författare)
Lewensohn, Rolf (författare)
Nygren, Peter, (författare)
Uppsala universitet, Institutionen för medicinska vetenskaper, Cancer Pharmacology and Informatics
De La Torre, Manuel (författare)
Luthman, Kristina (författare)
Larsson, Rolf, (författare)
Uppsala universitet, Institutionen för medicinska vetenskaper, Cancer Pharmacology and Informatics
visa färre...
Uppsala universitet Medicinska och farmaceutiska vetenskapsområdet. Medicinska fakulteten. Institutionen för medicinska vetenskaper. (creator_code:org_t)
Göteborgs universitet Naturvetenskapliga fakulteten. Institutionen för kemi. 
2004
Engelska.
Ingår i: Investigational new drugs. - 0167-6997. ; 22:4, s. 411-20
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • The novel alkylating dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 micromoles/kg, was considered close to this level, with minor effects on body weight gain but significant effects on hematological parameters. Melphalan and J1 appeared equitoxic with no statistically significant differences. Subsequently a mouse hollow fiber model was employed with subcutaneous implantation of fibers containing human tumor cells. Three different human tumor cell lines as well as two samples of primary human tumor cells (ovarian carcinoma and chronic lymphatic leukemia) were used as tumor models. At the dose level tested there was a marked and statistically significant decrease in both T-cell leukemia CCRF-CEM and small cell lung cancer NCI-H69 tumor cell growth and viability in response to J1 as compared with both placebo and melphalan treated groups. In primary ovarian carcinoma cells only J1 treatment resulted in significant tumor regression (net cell kill). In summary the results indicate that, despite an expected short half time in the blood circulation, the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation. At equal doses of alkylating units J1, compared to melphalan, was more active in the mouse hollow-fiber model, but showed similar general toxicity.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska grundvetenskaper -- Läkemedelskemi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Nyckelord

Acute Toxicity Tests
Animals
Antineoplastic Agents
Alkylating
pharmacology
toxicity
Cell Line
Tumor
Dipeptides
pharmacology
toxicity
Dose-Response Relationship
Drug
Drug Screening Assays
Antitumor
Humans
Male
Melphalan
pharmacology
Mice

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