azaserine and Colonic-Neoplasms

A review of the clinical data on azaserine, DON, and azotomycin reveals that these agents have limited but definite antitumor activity. All three drugs are analogs of L-glutamine and contain a diazo group. They have been studied as single agents in a wide variety of human malignancies and have also been included in trials using combination chemotherapy. Most of these studies were performed early in the history of clinical trials and, therefore, the method of reporting results and the evaluation criteria were quite different from those in use today. A renewed interest in these agents has been triggered by the remarkable activity of DON and azotomycin against human tumor lines implanted into nude mice. On the basis of this activity and the clinical data we have compiled, we feel that new clinical trials with these agents are warranted.

Topics: Animals; Antineoplastic Agents; Azaserine; Azo Compounds; Colonic Neoplasms; Diazooxonorleucine; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Transplantation, Heterologous

Topics: Anemia; Asparaginase; Azaserine; Breast Neoplasms; Clinical Trials as Topic; Colonic Neoplasms; Drug Combinations; Humans; Hydroxyurea; Leukopenia; Lung Neoplasms; Melanoma; Neoplasms; Rectal Neoplasms; Remission, Spontaneous; Stereoisomerism; Stomach Neoplasms; Thrombocytopenia

Keratin is a member of the intermediate filament family in epithelial cells. Two-dimensional gel electrophoresis of different epithelial cells has shown 20 different keratin polypeptides. Therefore, mapping of the keratin polypeptides can be used to define a specific tissue.. Cytokeratin expression was investigated by using monoclonal antibodies in human surgical specimens and autopsy material of pancreatic, gastric, liver, and colon carcinomas and cholangiocarcinomas, and their metastasis to lymph nodes and liver was examined. In addition, rat acinar cell carcinomas were used to compare cytokeratin expression in ductal vs. acinar cell pancreatic carcinomas.. Human pancreatic ductal carcinomas expressed keratins 7, 8, 18, and 19, whereas the majority of rat acinar carcinomas did not express keratins typical for ducts in rat pancreas. The keratin patterns of gastric and colon carcinomas were identical with keratins 8, 18, and 19. In contrast, hepatocellular carcinomas expressed the same keratin pattern as pancreatic acinar carcinomas with keratins 8 and 18, whereas cholangiocarcinomas expressed keratin 7, 8, 18, and 19, similar to pancreatic ductal carcinomas. Metastasis of pancreatic ductal and colon carcinomas retained their keratin patterns.. Keratin polypeptide typing of unknown malignant cells can be a useful tool for cell identification.

Topics: Animals; Azaserine; Carcinoma, Acinar Cell; Carcinoma, Ductal, Breast; Colonic Neoplasms; Epithelium; Gastrointestinal Neoplasms; Humans; Immunohistochemistry; Intermediate Filaments; Keratins; Male; Neoplasms, Experimental; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Stomach Neoplasms

The intratumoral content of 5-phosphoribosyl 1-pyrophosphate (PRPP) and the activity of the enzymes anabolizing and catabolizing the sugar phosphate were determined following i.p. administration of an LD10 dose of an L-glutamine antagonist or saline to tumor-bearing animals. Elevation of PRPP pool size following administration of L-[alpha S,5S]-alpha-amino-3-chloro-4,5-dihydro-5-isopazoleacetic acid (NSC-163501) (AT-125) was maximal at 8 hr and returned to pretreatment levels by 24 hr. In P388 leukemia, dose for dose, at 4 hr, 6-diazo-5-oxo-L-norleucine (NSC-7365) (DON) was the most potent of the L-glutamine antagonists in elevating basal PRPP pool size (50% above control) followed by AT-125 and azaserine, 300 and 100% above control respectively. Moreover, such augmentation in PRPP pool size preferentially affected P388 tumor rather than the small intestine. Following i.p. administration of LD10 doses of AT-125, DON and azaserine, the specific activities of PRPP anabolizing and catabolizing enzymes were determined. A significant inhibition of PRPP amidotransferase was demonstrated with DON and AT-125 (P less than 0.05), and no inhibition with azaserine. A similar modulation of PRPP pool size demonstrated in vivo following administration of 250 mg/kg of ART-125 in mice bearing colonic adenocarcinoma lines. It was suggested that a significant increase of PRPP pool size might cause the possible synergism of a selected L-glutamine antagonist and 5-fluorouracil as reported after the appropriately scheduled administration of methotrexate and 5-fluorouracil.

Topics: Adenocarcinoma; Animals; Azaserine; Colonic Neoplasms; Diazooxonorleucine; Glutamine; Intestine, Small; Isoxazoles; Leukemia P388; Leukemia, Experimental; Mice; Neoplasms, Experimental; Pentosephosphates; Phosphoribosyl Pyrophosphate

Forty-seven substances were tested for antitumor activity against the McCall rat colon adenocarcinoma. The most effective compounds were mitomycin C, 1,1', 1"-phosphinothiolylidynetrisaziridine and adriamycin. Others less active were azaserine, N-(4-chlorophenyl)-N'-(1-methylethyl)-imidodicarbonimidic diamide and 3,6-bis(5-chloro-2-piperidinyl)-2,5-piperazinedione. A number of standard anticancer drugs, 5-fluorouracil, arabinosylcytosine, methotrexate, bleomycin, daunomycin, 6-mercaptopurine, cis-dichlorodiammine platinum(II), cyclophosphamide and actinomycin D, were not effective under the test conditions and evaluation procedure used. Lentinan, though causing no initial inhibition of growth, did cause some regression. Significant synergism in terms of regression was seen in combination therapy with mitomycin C and azaserine.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Azaserine; Colonic Neoplasms; Drug Therapy, Combination; Male; Mitomycin; Mitomycins; Neoplasms, Experimental; Rats; Rats, Inbred Strains