Biomedical subjects

J A Double

Publications and source records attributed to J A Double.

94 records · Page 6Linked to original sources

PubMedDate not supplied

Chemotherapy of transplanted adenocarcinomas of the colon in mice.

Transplantable adenocarcinomas of the colon in mice have been developed from primary tumors induced by 1,2-dimethylhydrazine. Two such transplant lines, MAC-13 and MAC-15, have been used to assess the possible value of this type of tumor in chemotherapy screening. A protocol has been established and 11 standard drugs were tested against the two lines. Both tumors show sensitivity which is remarkably similar to that of human large bowel cancer, and MAC-13 would have correctly predicted the activity in man for ten of the 11 drugs. Quantitatively, CCNU, methyl-CCNU, and cyclophamide were the most effective drugs. A comparison of the predictive efficiencies of L1210 leukemia, B16 melanoma, and these new tumors as screening systems for colorectal cancer is made and discussed.

Adenocarcinoma↗

PubMedDate not supplied

Vinflunine potentiates the activity of cisplatin but not 5-fluorouracil in a transplantable murine adenocarcinoma model.

BACKGROUND: Vinflunine is a novel Vinca alkaloid currently undergoing Phase II clinical trials, which have previously demonstrated anti-vascular effects in a transplantable murine colon adenocarcinoma model. Previous studies with compounds showing similar effects in combination with standard anti-cancer agents have demonstrated an improved efficacy relative to the standard agents. MATERIALS AND METHODS: In this study the synergistic effects of administering vinflunine in combination with either Cisplatin (CPL) or 5-fluorouracil (5-FU) were investigated in a well-differentiated transplantable murine colon adenocarcinoma model (MAC 29). RESULTS: Vinflunine significantly potentiated the anti-tumour effects of CPL, but had little effect in combination with 5-FU. Using Hoescht 33342 dye labelling of the functional vasculature, clear evidence of vascular shutdown was seen for treatment groups including vinflunine. CONCLUSION: These data demonstrate that the combination of vinflunine and CPL has significant preclinical anti-tumour activity against a transplantable murine adenocarcinoma model that is related to the anti-vascular effects of vinflunine.

Adenocarcinoma↗

PubMedDate not supplied

Antitumor activity of imidazothioxanthones in murine and human tumor models in vitro and in vivo.

BACKGROUND: A new series of imidazothioxanthones has recently been synthesized as potential anticancer agents with the aim of overcoming drug resistance. The route of synthesis and DNA-binding properties of the compounds were reported previously. This paper describes the general structure-activity relationships for the class of imidazothioxanthones in panels of human and murine tumor cell lines in vitro, and the in vivo activity against human and murine solid tumors of the most potent compound, N-[3-(Dimethylamino)propylo]-11-oxo-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide (10a). In addition, the interaction between compound 10a and DNA is also considered in terms of molecular mechanics methods and flexible docking techniques. MATERIALS AND METHODS: The cytotoxicity of compounds 10a, 11-oxo-N-[2-(pyrrolidino)ethylo]-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide, 11-oxo-N-[2-(piperidino)ethylo]-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide and N-[2-(morpholino)ethylo]-11-oxo-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide (10c-10e) was assessed in human tumor cell lines and xenografts using the sulforhodamine B assay, MTT assay and the clonogenic assay. The human ovarian xenograft, PXN/109TC, two human breast carcinomas, MT-1 and MCF-7, and the murine colon adenocarcinoma, MAC15A were used for the in vivo testing of compound 10a. In addition, the interaction between compound 10a and DNA is also considered in terms of molecular mechanics methods and flexible docking techniques. RESULTS: Two compounds, 10a and 10c, showed cytotoxic activity below 10 mM in the NCI in vitro screen of 60 human tumor cell lines. The IC50 value of compound 10a was 6.8 mM and that of 10c, 8.3 mM. In addition, both compounds possessed differential activity against leukemia, colon and mammary cancer. The activity pattern was confirmed in two further screens using monolayer and clonogenic, assays. In vivo antitumor studies showed that 10a was active against the human mammary carcinoma MT-1 and murine colon cancer MAC15A. Marginal activity was observed in human ovarian cancer model PXN/109T/C and the compound was inactive in human mammary cancer MCF-7. CONCLUSION: The results warrant further in vivo testing of 10a in additional human solid tumor models. The molecular modeling showed that the planarity of the chromophore and the side-chain conformation could assist the insertion of compound 10a between the base pairs of the double helix. On the other hand, docking to the nucleotide sequence GGAATTGCCTCA suggested that the molecule could also act as a minor groove binder.

Adenocarcinoma↗

PubMedDate not supplied

Anti-tumour activity and bone marrow toxicity of chloroethylnitrosocarbamoyl-amino acid derivatives.

The anti-tumour activity of a series of chloroethylnitrosoureas derived from the amino acids alanine and glycine was examined in 3 transplantable adenocarcinomas of the mouse colon. In addition, bone marrow toxicity was assessed using a spleen colony forming unit assay. A spectrum of differing activity-toxicity patterns was demonstrated. At one extreme CNC-glycinemethylamide was shown to exhibit activity against all 3 tumour lines but at the expense of profound bone marrow damage. The other end of the spectrum was represented by CNC-alanylalanine which produced high activity only against the ascitic tumour following intraperitoneal drug administration but in the absence of marrow damage. However, oral administration of this drug led to decreased anti-tumour activity and increased marrow toxicity. These results suggested that differences in the pharmacokinetic behaviour of these compounds were responsible for the differing activity-toxicity patterns. The activity-toxicity pattern exhibited by CNC-alanylalanine indicated that it was a possible candidate for the treatment of local intra-cavitary disease.

Amino Acids↗