Comparison of intramural 5-fluorouracil and more conventional routes of drug administration on concentrations in gastric regional lymph nodes: a potential for trans-endoscopic adjuvant chemotherapy.

Intramural injection of 20 muCi (2-14C) 5-fluorouacil (5-FU) into the gastric submucosa of dogs and baboons was employed to evaluate the kinetics of 5-FU distribution following this route of administration and to compare these results with those following intraluminal, intravenous, and local intraarterial injections. Measurements of radioactivity taken over a six-hour period after injections demonstrated that the greatest concentration of isotope in samples of gastric wall and perigastric lymph nodes was found after administration of the drug directly into the stomach wall. Clinical application of intramural injections of 5-FU into the stomach wall under direct gastroscopic visual control, may be worthy of trial in patients with gastric cancer.

A study of the effect of papaverine in neuroblastoma using the experimental C1300 murine system.

The effect of papaverine on transplantable C1300 murine neuroblastoma model was evaluated. Subcutaneous inoculation of A/J mice with 10(6) C1300 cells resulted in predictable tumor growth and animal death in 36 +/- 5 days. In 33% of control animals, lung and liver metastases were observed. Subcutaneous injections of papaverine prior to tumor inoculation and during the tumor growth failed to show any detectable effect on local growth of the tumor. Benign transformation of the primary tumor was not observed. However, papaverine injection 21 days after tumor inoculation was associated with only 9% incidence of metastatic development. Papaverine treatment, when started one day prior to tumor inoculation or 10 days after tumor implant, resulted in complete prevention of all detectable metastatic growth, while having no apparent effect on local tumor growth. Further study of papaverine effect in the neuroblastoma murine model is indicated.

The value of levamisole in a Wilms' tumor animal model.

The effect of Levamisole was studied in an animal model of Wilms' tumor. No tumoridical effect of Levamisol could be documented in this tumor model, and no effect was shown on prevention of tumor, when Levamisole was given before tumor implantation. In previous experience with Wilms' tumor model, a good correlation between the human and animal tumor was found in regard to treatment with different drugs. The fact that Levamisole had no effect on our animal model and its reported immunosuppressive effect at some doses, should be considered in planning clinical trials.

Pharmacokinetic studies of a transplantable murine renal adenocarcinoma.

An animal model to investigate new therapeutic approaches for the treatment of renal adenocarcinoma has been further studied. This model is based on a transplantable murine renal adenocarcinoma whose growth follows Gompertzian kinetics, relates to tumor RNA and DNA content, and also correlates with the rate of tumor DNA synthesis. This model in the current study was also evaluated for the ability of various therapeutic agents to inhibit tumor DNA synthesis. Such tests may be valuable for the preclinical screening of potentially useful drugs and may provide insight into fundamental aspects of tumor control. In this study, CCNU, BCNU, and adriamycin were potent inhibitors of tumor DNA synthesis whereas cytosine arabinoside, bleomycin, and cyclophosphamide were not. These observations were confirmed by autoradiography and correlated with other experimental end points of tumor therapy such as tumor weight and animal survival. This preclinical screening model is an effective and helpful means whereby new drugs and drug combinations can be tested for potential use in human renal cell carcinoma.

Some new approaches to potential test systems for drugs against prostatic cancer.

We have previously reported on test systems, based on 5alpha-reductase (5alpha-RA) and arginase activities and steroid deposition in animal prostates, potentially useful in screening drugs possibly effective in cancer of the prostate. Recently, we have concentrated on the development of other in vivo and in vitro systems which may prove of further value in testing such drugs. These systems include the following: (a) The effects of drugs on 5alpha-RA activity in human and animal non-malignant and human cancerous prostatic tissues in organ culture. The parameters necessary for the maintenance of optimal 5alpha-RA in such explants have been determined, and it has been shown that certain agents (estramustine phosphate, progesterone, estradiol-17beta) can inhibit 5alpha-RA under in vitro conditions, pointing to the potential use of such an approach in screening various cytostatic agents. In addition, 65Zn deposition, the histology, and the androgen metabolism in such tissues in organ culture are being determined as additional parameters. (b) The deposition of 65Zn in the rat dorsolateral gland, particularly as affected by prolactin and testosterone, and the effects of chemotherapeutic agents on such deposition. Methotrexate and CCNU have been shown to be potent inhibitors of 65Zn deposition in the dorsolateral gland. The parameters related to zinc metabolism in the prostate are being further investigated. (c) The demonstration of receptors for estrogens (estradiol-17beta, diethylstilbestrol) in the prostate of the baboon. The various parameters related to the specificity of such receptors have been established. The development and standardization of these approaches, some facets of which are reported in the present publication, may prove them to be more sensitive, specific, and optimal than other systems and should afford an opportunity to test various combinations of drugs potentially useful in cancer of the prostate with relative speed, efficacy, and ease of manipulation.

5alpha-Reductase as a target enzyme for anti-prostatic drugs in organ culture.

Short-term organ culture of rat and human prostatic tissues has been utilized as a means of testing drlgs potentially useful in cancer of the prostate. Optimal conditions, particularly the concentration of T, have been established for organ culture of such tissues and the effects of various drugs on 5alpha-reductase activity (5alpha-RA) have been utilized as a means of ascertaining antiprostatic actions of the various compounds and drugs tested. Thus, it was shown that estracyt, estradiol-17beta, progesterone, and novel steroids and steroid-conjugates have definite effects on 5alpha-RA in this system.

Potential test systems for drugs against prostatic cancer.

A number of chemotherapeutic agents have been tested in two systems which could be useful as models in the search for effective drugs for cancer of the prostate. One system involved the effects of the administered drugs on rat prostatic 5 alpha-reductase and arginase activities. Since both enzymic systems are androgen dependent and essential for prostatic function and anatomy, the effectiveness of a drug in these systems could be indicative of its value in the treatment of prostatic cancer. Michaelis constants were obtained with Lineweaver-Burk plots and the conclusions are based on a comparison of these plots with those of the controls. Thus, the following results were obtained: (a) isophosphamide, bleomycin, and procarbazine produced definite inhibition of 5 alpha-reductase in either or both the ventral and dorsolateral glands of the rat; (b) 5-fluorouracil, vincristine, bleomycin, procarbazine, adriamycin, and hexamethyl-melamine inhibited arginase activity significantly in both glands; (c) streptozotocin and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388) produced inhibition of arginase in the ventral gland only; (d) in contrast to the noncompetitive or uncompetitive inhibition of most of the drugs, particularly in the ventral gland, procarbazine, hexamethylmelamine, bleomycin, adriamycin, and NSC-45388 produced competitive inhibition of arginase in the dorsolateral gland; and (e) seven of the drugs led to an activation of 5 alpha-reductase (5-fluorouracil, vincristine, NSC-45388, hexamethylmelamine, CCNU, streptozotocin, and diglycolaldehyde). The second model system utilized the deposition of labeled estriol and testosterone in the dog prostate and the effects of drug therapy as a possible index of effectiveness in prostatic cancer. Streptozotocin and procarbazine definitely interfered with the deposition of both estriol and testosterone. On the basis of the data obtained, the model systems investigated by us could potentially serve as reliable indicators for the clinical use of drugs against cancer of the prostate.