Search PubMed⌕ Search

Biomedical subjects

J A Double

Publications and source records attributed to J A Double.

At least 73 records · Page 4Linked to original sources
PubMed1988

Unique chemosensitivity of MAC 16 tumours to flavone acetic acid (LM975, NSC 347512).

MAC 16 is one of a series of mouse colon tumours originally induced by dimethylhydrazine. It is a relatively slow growing subcutaneous adenocarcinoma which becomes necrotic as it grows and causes severe body wasting in the host. This study has indicated that the tumour is resistant to a large number of standard anti-cancer drugs but is highly responsive to the investigational agent flavone acetic acid (FAA). The levels of FAA achieved in tumours are lower than those necessary for activity in vitro suggesting its mechanism of action in vivo is not direct cytotoxicity. Responding tumours demonstrate massive tissue necrosis and those which are not cured have viable tumour cells associated with tumour blood vessels. The anti-tumour effects are accompanied by control of the host's cancer cachexia. The unique chemosensitivity of MAC 16 to FAA suggests that this agent has a novel mechanism which may be dependent upon specific biological characteristics of tumours.

Adenocarcinoma↗
PubMed1987

Influence of the tissue distribution of ThioTEPA and its metabolite, TEPA, on the response of murine colon tumours.

Disposition studies in the same animals as those used for assessment of antitumor and toxic effects could increase understanding of the variation in response to cytotoxic drugs. Tissue and plasma levels of ThioTEPA and triethylenephosphoramide (TEPA) were measured to see if any correlation existed between them and the effects of the drug on a series of mouse colon tumours (MAC). The tumour panel included an ascitic form (MAC 15A), an anaplastic (MAC 13) and a well-differentiated (MAC 26) solid tumour, all grown subcutaneously. The maximum tolerated dose of ThioTEPA was 20 mg kg-1 in females bearing MAC 13 and 15 mg kg-1 in males having MAC 15A or 26. The diverse growth characteristics of the tumour cell lines necessitated the use of different methods for assessment of response. After administration of the maximum tolerated dose, the greatest response was observed in MAC 26, in which a growth delay of 15 days-twice the doubling time of the tumour volume-occurred. ThioTEPA produced 58% inhibition of MAC 13 tumour weight, but MAC 15A was unresponsive. One hour after intraperitoneal administration of Thio-TEPA (20 mg kg-1), ratios of tissue to plasma concentration were 1.13, 0.87 and 1.17 in tumours and 0.80, 0.75 and 0.73 in spleens of mice bearing MAC 13, 15A and 26 respectively. These data show greater accumulation of drug in neoplastic than in normal tissues. The pattern of distribution of the metabolite was similar, but there was a lesser degree of tissue accumulation than by the drug. Concentrations of drug and metabolite in neoplastic tissues related to their protein content were 116.0, 126.3 and 183.3 micrograms ThioTEPA/g and 57.5, 83.1 and 78.6 micrograms TEPA/g in MAC 13, 15A and 26 respectively. Combination of these chemosensitivity and pharmacokinetic data indicates that differences in response of these tumours to ThioTEPA cannot be explained by the availability of the drug and metabolite. The therapeutic effects of ThioTEPA cannot be predicted purely from a knowledge of drug and metabolite disposition.

Adenocarcinoma↗
PubMed1987

Factors involved in the anti-cancer activity of the investigational agents LM985 (flavone acetic acid ester) and LM975 (flavone acetic acid).

LM985 has been shown previously to hydrolyse to flavone acetic acid (LM975) in mouse plasma and to produce significant anti-tumour effects in transplantable mouse colon tumours (MAC). It has undergone Phase I clinical trials and dose limiting toxicity was acute reversible hypotension. Substantially higher doses of LM975 can be given clinically without dose limiting toxicity. We have investigated the activity of LM975 against a panel of MAC tumours and also the in vitro cytotoxicity of both LM985 and LM975 in two cell lines derived from MAC tumours. LM985 is considerably more cytotoxic than LM975 in vitro but increased length of exposure to LM975 results in improved activity. Single in vivo injection of LM975 showed no activity against the ascitic tumour MAC 15A, moderate activity against the s.c. poorly differentiated tumour MAC 13 and produced a significant growth delay in the well differentiated MAC 26. These latter responses were considerably enhanced by repeated injection 7 days later. Pharmacokinetic studies in mice following i.p. injection of LM985 demonstrated rapid degradation of LM985 to LM975 in the peritoneum. Length of exposure as well as drug concentration appear important factors in determining anti-tumour responses.

Adenocarcinoma↗
PubMed1987

Characterization of a transplantable adenocarcinoma of the mouse colon producing cachexia in recipient animals.

MAC16 is a chemically induced, transplantable adenocarcinoma of the colon passaged in inbred NMRI mice. At small tumor burdens (less than 1% of the host weight), weight loss was observed without a reduction in food intake. As the tumor mass increased, weight loss also increased and reached 33% of host body weight in females and 20% in males when compared with the weight of age-matched controls. The reduction in host body weight was directly proportional to the tumor size and was reversible when the tumor was excised. There was a preferential loss of body fat in tumor-bearing animals with an increase in the plasma level of free fatty acids, although there was a minimal elevation of ketone bodies. Tumor growth was accompanied by progressive hypoglycemia and a reduction in the plasma insulin levels. The decrease in plasma insulin may have contributed to the catabolic effects of progressive tumor growth.

Adenocarcinoma↗
PubMed1986

Activity of N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-alanine and derivatives against transplantable adenocarcinomata of the mouse colon (MAC).

The anti-neoplastic activity of N-[N'-(2-chloroethyl)-N-nitrosocarbamoyl(CNC)]-alanine, CNC-alanyl-alanine, CNC-alanine-methylamide and CNC-glycine-methylamide was examined in murine transplantable colon tumours (MAC). The methylamide derivatives were highly active against a solid adenocarcinoma (MAC 13) and an ascitic adenocarcinoma (MAC 15 A). CNC-alanyl-alanine was also highly active against MAC 15 A. Responses of the three latter agents against the ascitic tumour were better than for any previously tested drugs including the nitrosoureas but their eventual usefulness cannot be determined without further toxicological studies.

1,2-Dimethylhydrazine↗
PubMed1986

Pharmacokinetics and anti-tumour activity of LM985 in mice bearing transplantable adenocarcinomas of the colon.

LM985 is one of a series of compounds based on the flavone ring structure and selected for clinical trial primarily for its activity in colon 38 as part of the NCI screen. We have investigated the anti-tumour activity against three differing transplantable adenocarcinomas of the mouse colon (MAC). Single i.p. injection at maximum tolerated dose showed no activity against the ascitic tumour MAC 15A, moderate activity against subcutaneous tumours MAC 13 and MAC 15A and produced a significant growth delay against MAC 26. These responses against s.c. tumours were considerably enhanced by repeated injection 7 days later when greater than 90% tumour inhibition was seen in MAC 13 and cures were achieved in MAC 26. Pharmacokinetic studies confirm the rapid degradation of LM985 to LM975, the possible active principle. Analysis of area under the curve for LM975 indicated a good relationship with administered doses of LM985 and tumour responses. The MAC system shows a good correlation with human large bowel cancer and these preliminary observations with LM985 would suggest that it or its metabolite LM975 may have a value in the management of large bowel cancer.

Adenocarcinoma↗
PubMed1986

Nucleoside analogues. 5. Molecular combination of anti-cancer drugs: activity of 5-fluorouracil/nitrosourea combinations against mouse colon tumours.

Anti-tumour activity of a novel series of molecular combinations, seco-nucleosides where the carrier is a sugar-like fragment linking the pyrimidine anti-metabolite 5-fluorouracil (5-FU) with the alkylating agent N-chloroethyl-N-nitrosourea (CNU), is presented. Three tumour lines, from the mouse adenocarcinoma of the colon (MAC) series, with different sensitivities to 5-FU and CNU were employed. All four molecular combinations tested showed some activity in this system. B 3839, in which 5-FU is linked by a SC--N bond, showed greatest activity against the ascitic tumour MAC 15A but was inactive at non-toxic doses against the solid tumour MAC 13. Activity against MAC 15A was of the same order as that achieved with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea. In contrast B 3958, with an OC--N bond, proved inactive against the ascitic tumour but was highly active against MAC 13. The factors responsible for this reversal are as yet unknown.

Animals↗
PubMed1985

Gas chromatographic analysis of triethylenethiophosphoramide and triethylenephosphoramide in biological specimens.

Comprehensive pharmacokinetic studies could realise a greater potential for the antitumour agent triethylenethiophosphoramide (ThioTEPA), and these would be aided by the development of a selective and sensitive assay. After extraction of ThioTEPA and its metabolite, triethylenephosphoramide (TEPA), from plasma using Sep-Pak C18 cartridges, the compounds were separated by capillary chromatography, detected using a nitrogen detector and quantified by reference to an internal standard, hexaethylphosphoramide. The limits of sensitivity were 1-5 ng/ml. Analytical recoveries were 74 and 95%, for TEPA and ThioTEPA, respectively, in the therapeutic range. At similar concentrations, extents of protein binding, determined by ultrafiltration, were not significant. Preliminary investigations of the elimination of ThioTEPA show that drug loss occurs more quickly in mice than in humans and in both species the metabolite is extensively recycled.

Animals↗
PubMed1982

The assessment of response of murine transplantable colon tumors to combination chemotherapy.

The mouse adenocarcinoma of the colon (MAC) system, which has been shown to be a good model for human colorectal carcinoma in terms of its chemosensitivity, was tested with two modified human protocols (MeCCNU + 5 FU, BCNU + 5 FU) in an attempt to evaluate its suitability as a model for developing new regimens of combination chemotherapy for treating patients with colorectal carcinoma. This attempted evaluation raised problems regarding, firstly, the length of time available before tumours became too large in control and non-responding hosts to maintain adequate mobility and, secondly the assessment of response to the drugs. The commencement of drug administration 3 days after transplantation and the assessment of response by measuring delay in time for tumor growth to reach a given volume, with the results analysed by Gehan's (generalised Wilcoxon) test, gave a workable method of evaluation. This method is presented as being suitable for use in the study of transplantable solid tumor lines as models for combination chemotherapy.

Adenocarcinoma↗
PubMed1981

Effects of nandrolone decanoate on the toxicity and anti-tumour action of CCNU and FU in murine tumours.

Pre-treatment with the anabolic steroid nandrolone decanoate (ND) increases the LD50 of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 5-Fluorouracil (FU) in NMRI mice. Administration of ND did not affect the anti-tumour action of CCNU against a transplantable mouse adenocarcinoma of the colon (MAC 13) or the anti-tumour action of FU against MAC 26. In both tumour lines ND had no significant effect on tumour growth. These data suggest that an increase in the anti-tumour selectivity of these agents may be produced by pre-treatment with ND.

Adenocarcinoma↗
PubMed1980

Some biological characteristics of transplantable lines of mouse adenocarcinomas of the colon.

During a 5-year period colon tumors induced by 1,2-dimethylhydrazine dihydrochloride treatment in NMRI mice were transplanted sc into isologous mice to obtain transplantable tumor lines that might serve as experimental models for human colon cancer. The resultant 17 serially transplantable tumor lines were adenocarcinomas varying in degree of differentiation and mucin production. Two of the lines passaged for 5 years and used in chemotherapy studies have shown histologic progression toward dedifferentiation with concomitant acceleration of growth rate.

Adenocarcinoma↗
PubMed1978

Drug latentiation in cancer chemotherapy.

Latent antitumour agents require spontaneous or enzyme-catalysed activation to cytotoxic species in vivo. Activation may occur principally in normal tissues or in the target tumour. Agents of this type are discussed and mechanisms of drug action and selectivity are described, with reference to appropriate examples. The comparatively poor therapeutic activity of many agents designed for selective activation in tumours is attributed to the often unfavourable distribution of activating enzymes between normal and neoplastic tissues. Factors to be considered in the design of new enzyme-activated agents are discussed and possible artefacts involved in the assay of tumour enzymes are described. Some novel approaches to the design of latent antitumour agents are also discussed.

Animals↗