Inhibition of papilloma formation by analogues of 7,8-dihydroretinoic acid.

The design of analogues of 7,8-dihydroretinoic acid (7,8-dihydro-RA) was based on reported biological activities of this retinoid and its dihydro-TMMP(1) analogue and on structural hypotheses. 7-Oxa-7,8-dihydroretinoids (5, 6) were prepared by O-alkylation of phenoxides by methyl 8-bromo-3,7-dimethyl-2,4,6-octatrienoate. In some cases, C-alkylation also occurred.

Biodistribution of radiolabeled lipid-DNA complexes and DNA in mice.

The tissue biodistribution and expression of [33P]DNA-1-[2-[9-(Z)-octadecenoyloxy]ethyl]]-2-[8](Z)-heptadece nyl]-3 -[hydroxyethyl]imidazolinium chloride (DOTIM):cholesterol complexes and 33P-radiolabeled DNA expressing chloramphenicol acetyl transferase (CAT; 4.7 kB) were studied after intravenous (iv) injection in ICR mice. Mice were injected with 200 microL of complex containing DNA at 3 mg/kg or DNA alone.

Conformationally defined retinoic acid analogues. 4. Potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias.

We recently synthesized several conformationally constrained retinoic acid (RA) analogues [8-(2'-cyclohexen-1'-ylidene)-3, 7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R1) and 3' (R2) positions on the cyclohexene ring] (Muccio et al. J. Med.

Conformationally defined 6-s-trans-retinoic acid analogs. 3. Structure-activity relationships for nuclear receptor binding, transcriptional activity, and cancer chemopreventive activity.

We recently demonstrated that conformationally defined 6-s-trans-retinoic acid (RA) analogs were effective in the prevention of skin papillomas (Vaezi et al. J. Med.

Murine toxicology and pharmacology of UAB-8, a conformationally constrained analog of retinoic acid.

(2E, 4E, 6E)-8-[3'-Ethyl-2'-(1-methylethyl)-2'-cyclohexen-1'-ylidene] -3, 7-dimethyl-2,4,6-octatrienoic acid (UAB-8) has potent activity in preventing papillomas on the skin of mice similar to that determined in a previous study for the homolog containing one less carbon atom. To evaluate the toxicological profile for UAB-8, relative to all-trans-retinoic acid (RA), female mice were dosed by oral gavage for 29 days with amounts of 0.05, 0.

A conformationally defined 6-s-trans-retinoic acid isomer: synthesis, chemopreventive activity, and toxicity.

A conformationally defined retinoic acid analog (1) which contains a dimethylene bridge to maintain the 6-s-trans orientation for two terminal double bonds in the polyene chain was synthesized. A Reformatsky reaction was utilized to extend the polyene chain of the starting enone, which provided exclusively the 9Z-configuration for the intermediate aldehyde. A Horners-Emmons condensation with this aldehyde then produced retinoic acid analogs with both 9Z- and 9Z,13Z-configurations.

Diversity of penetration of anti-cancer agents into solid tumours.

Failure of anti-cancer agents to reach all clonogenic cells at cytotoxic concentrations is recognized as an important form of resistance in solid tumours. Subcutaneously implanted mammary adenocarcinoma 16/C was used to evaluate the intratumour distribution of five alkylating, bioreductive alkylating and intercalating agents and two radiation sensitizers. The agents were classified according to their in vivo distribution in well- and poorly-perfused tumour regions, as delineated by lissamine green.

Distribution of adriamycin in mice bearing mammary adenocarcinoma 16/C.

The response of solid mammary adenocarcinoma 16/C to treatment with Adriamycin is highly variable and ranges from growth under treatment to complete regression. Tumour and host factors were evaluated to determine the influence of each on the response. We determined that the concentration of Adriamycin in plasma and tumour was a function of tumour size and treatment history in mice bearing mammary adenocarcinoma 16/C.

Variability of tumor response to chemotherapy. II. Contribution of tumor heterogeneity.

The role of tumor-to-tumor variability in response to chemotherapy was investigated in mice bearing mammary adenocarcinoma 16/C treated with melphalan. Lissamine green, a triphenylmethane dye, was given systemically to delineate areas of perfusion in the tumors. The regions of low perfusion ranged from less than 10% to greater than 90% of the mass of individual tumors.

Variability of tumor response to chemotherapy. I. Contribution of host heterogeneity.

Host factors that might be associated with the variable response of tumors to effective chemotherapy were studied in B6C3F1 mice bearing transplanted mammary adenocarcinoma 16/C tumors and treated with melphalan. Tumor response ranged from regression to an unpalpable size to growth under treatment. That biochemical resistance of the cell population was not primarily responsible for the variability was demonstrated by passage of responsive and nonresponsive tumors into new hosts followed by treatment with melphalan.

Distribution of nitroimidazoles and L-phenylalanine mustard in mammary adenocarcinoma 16/C tumors.

Using the triphenylmethane dye, lissamine green, as an indicator of blood perfusion, we have demonstrated that L-phenylalanine mustard (L-PAM) is differentially distributed in mice bearing mammary adenocarcinoma 16/C tumors. Following i.p.

Tumor dependence of observed thymidine index as a function of emulsion exposure.

The graphs of observed pulse thymidine index against duration of emulsion exposure for seven experimental tumor systems have been observed to exhibit significant differences; either they were parallel and displaced, or they were nonparallel. The immediate practical consequence of this phenomenon is that identical emulsion exposure times, other experimental conditions being equal, may not be sufficient to provide valid comparison of thymidine indices among tumors. A mathematical model is described which relates observed autoradiographic labeling index to the distribution of radioactive atoms among individual cells that initially incorporate labeled material.

The cell population kinetics and response to an S-phase specific agent of three transplantable colon tumor lines.

The relative cell population kinetics of three transplantable murine colon tumor lines (Colon 26, 36 and 38) with different histological and metastatic characteristics were studied in relation to the response of each line to an S-phase specific agent. The mean doubling times for the three lines between 0.1 and 1.

Studies of the growth, population kinetics, and host lethality of CD8F mammary adenocarcinoma.

First-generation transplants of spontaneous mammary adenocarcinomas in CDSF mice have been included in the tumor panel used for the screening of potential anticancer chemotherapeutic agents. Studies were undertaken to evaluate the growth and kinetic characteristics to provide a better understanding of the basic biology of the tumor system. The spontaneous mammary adenocarcinomas are highly variable in growth rate, and this characteristic is seen to a lesser extent in the transplanted tumors.

Effects of surgery on the cell kinetics of residual tumor.

Noncurative excision of a primary sc Lewis lung tumor performed on Day 7 or later results in an increase in the thymidine index and growth rate with minimal changes in the cell cycle parameters of the lung metastases. The stimulation of the lung nodules is accompanied by a small but consistent decrease in median lifespan. Sham surgery performed on Day 3 or later also results in a decrease in median lifespan and an increase in the thymidine index of the undisturbed primary tumor.

Ambiguity of the thymidine index.

The observed thymidine indices of seven experimental tumor lines are compared as a function of duration of emulsion exposure. The effects of dose level of tritiated thymidine and background threshold are also evaluated. The results indicate that an arbitrary high background threshold discriminates against "lightly" labeled cells at short periods of exposure but that the chosen threshold becomes less critical with longer exposure.

Basic and therapeutic trial results obtained in the spontaneous AK leukemia (lymphoma) model-end of 1971.

Basic and therapeutic trial results obtained in the spontaneous AK leukemia (lymphoma) model have been brought together for comparison with available information on the much used transplanted murine leukemia models and human leukemias and lymphomas. The etiologic agent for "spontaneous" AK lymphoma is an RNA virus present at birth in AKR mice. Lymphoma cells first appear in the thymuses of animals at 5-->12 months of age.