Original article Application of -aminoisobutyric acid, L-methionine, thymidine and 2-fluoro-2-deoxy-D-glucose to monitor effects of chemotherapy in a human colon carcinoma cell line Helmut Schaider 1, 2, Uwe Haberkorn 3, Martin R. Berger 2, Franz Oberdorfer 3, Iris Morr 3, Gerhard van Kaick 3 1 Department of Dermatology, KarI-Franzens University, Auenbruggerplatz 8, A-8036 Graz, Austria 2 Unit of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, Germany 3 Department of Oncologic Diagnosis and Therapy, German Cancer Research Center, Heidelberg, Germany Received 22 June and in revised form 16 September 1995 Abstract. Up to 4 h after treatment of human SW 707 colon carcinoma cells with the antineoplastic drug 4- amino-N-(2'-aminophenyl)-benzamide (GOE 1734, di- naline), the effects of tumour cell metabolism and prolif- eration were examined in vitro. Four tracers which can be labelled with isotopes suitable for positron emission tomography (PET) were used for this purpose: (x-amino- isobutyric acid (AIB) and methionine to study changes in amino acid transport and protein synthesis, thymidine to observe changes in tumour proliferation and 2-fluoro- 2-deoxy-D-glucose (FDG) to estimate glucose metabo- lism. Dinaline showed an inhibition of the sodium-de- pendent and -independent uptake of AIB. The methio- nine uptake was found to increase shortly after therapy. Thymidine incorporation into DNA was impaired and the FDG uptake showed a maximally 2.2-fold enhance- ment. Inhibition of AIB uptake suggests changes in ami- no acid transport, whereas increased uptake of methio- nine and FDG points to an enhancement of protein syn- thesis and glycolysis caused by repair mechanisms. The cytostatic and antiproliferative effect of dinaline, ob- served in cell growth curves, could be demonstrated by the impaired thymidine incorporation into DNA. This study demonstrates that in vitro screening with radio- tracers suitable for PET can help to clarify effects of new antineoplastic substances on tumour cell metabo- lism. These data may be applied to choose the appropri- ate time schedule for monitoring therapeutic effects on tumour tissue. Key words: c~-Aminoisobutyric acid - L-Methionine - Thymidine - 2-Fluoro-2-deoxy-D-(U-~4C)-glucose - Dinaline Eur J Nucl Med (1996) 23:55-60 Correspondence to: H. Schaider Introduction Currently used cytostatic drugs are able to achieve nor- mal life spans only in patients with certain types of can- cer. The responsive category does not include the most frequent forms of malignant tumour, but it includes neo- plasms with relatively short tumour volume doubling times. Benzamides represent a group of pharmacologi- cally active lipophilic compounds which were found to affect poly-ADP-ribosylation [1], glucose metabolism, DNA synthesis and cell viability [2]. 4-Amino-N(2'-ami- nophenyl)-benzamide (dinaline, GOE 1734) is a com- pound of this group and has been shown to be effective against slowly growing, chemically induced rat mamma- ry and colorectal carcinomas, osteosarcoma C22LR and Brown Norway myeloid leukaemia [3-7]. A cytostatic and cytotoxic effect of dinaline on various tumour cell lines in vitro has been demonstrated, but the precise mode of action has not yet been identified [8-10]. We have conducted a study to assess the effect of di- naline on tumour cell metabolism, amino acid transport and proliferation in vitro, c~-Aminoisobutyric acid (AIB), methionine, thymidine and 2-fluoro-2-deoxy-D- glucose (FDG) can be labelled with positron emitters and have been shown to be applicable for in vivo mea- surements [11-16]. Preclinical and clinical data support the feasibility of using such radiotracers to validate the response of cancers to chemotherapy [14-19]. To judge the effects of new antineoplastic drugs on tumour cell metabolism in vivo, in vitro studies with potential posi- tron emission tomography (PET) tracers could be of pre- dictive value for a better understanding of altered meta- bolic processes accompanying chemotherapy. Materials and methods Chemicals. 4-Amino-N-(2'-aminophenyl)-benzamide was kindly provided by G6deckeAG (Freiburg, Germany).3H-c~-aminoisobu- tyric acid (methyl 3H) (329.3 GBq/mmol; 8.90 Ci/mmol) was ob- tained from Du Pont, Nen Products (Boston, Mass.). 14C-L-me- European Journal of Nuclear Medicine Vol. 23, No. 1, January 1996 - © Springer-Verlag 1996