mercaptopurine and Carcinoma-256--Walker

A series of N-protected vinyl, 1,2-dihaloethyl, and cyanomethyl esters of phenylalanine was synthesized and these compounds were evaluated for antitumor activity against the growth of Ehrlich ascites carcinoma in CF1 male mice (33 mg/kg/day), Walker 256 carcinosarcoma in Sprague-Dawley male rats (2.5 mg/kg/day), and P388 lymphocytic leukemia in DBA/2 mice (20 mg/kg/day). Structure-activity relationships were evaluated and acute toxicity studies (LD50 determinations) in male CF1 mice were also carried out on selected compounds. Carbobenzoxy-L0phenylalanine vinyl ester (5), N-carbobenzoxy-L-phenylalanine 1,2-dibromoethyl ester (12), and N-carbobenzoxy-L-phenylalanine cyanomethyl ester (8) were found to be very potent inhibitors of Ehrlich ascites tumor growth at nontoxic doses cited above. Compounds 5 and 12 also tripled survival time in the Walker 256 system. LD50 values for compounds 5, 12, and 8 were greater than 2000 mg/kg (greater than 6.15 mmol/kg), 74 mg/kg (0.15 mmol/kg), and 150 mg/kg (0.44 mmol/kg), respectively.

Topics: Acetonitriles; Animals; Antineoplastic Agents; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Lethal Dose 50; Leukemia, Experimental; Male; Mice; Mice, Inbred DBA; Phenylalanine; Rats; Vinyl Compounds

Previously reported work on N-protected activated esters of phenylalanine has been extended to include N-protected vinyl, dibromoethyl, and cyanomethyl esters of several other amino acids. These compounds have been synthesized and evaluated in Ehrlich ascites carcinoma, Walker 256 carcinosarcoma, and and P388 lymphocytic leukemia tests. Among compounds tested were derivatives of tyrosine, tryptophan, glycine, leucine, proline, aspartic acid, glutamic acid, 4-aminobutyric acid, and 6-aminocaproic acid. Compounds of greatest potential interest from this study are N-carbobenzoxyglycine 1,2-dibromoethyl ester and N-carbobenzoxy-L-leucine 1,2-dibromoethyl ester. Both compounds were highly active in Ehrlich ascites test systems (33 mg/kg/day). The glycine derivative was also active in the Walker 256 test (2.5 mg/kg/day. Values for LD50's in mice were 148 mg/kg (0.37 mmol/kg) and 225 mg/kg (0.50 mmol/kg) for glycine and leucine derivatives, respectively; therefore, these compounds do not appear to be toxic at effective dose levels.

Topics: Acetonitriles; Amino Acids; Animals; Antineoplastic Agents; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Lethal Dose 50; Leukemia, Experimental; Mice; Structure-Activity Relationship; Vinyl Compounds

Evidence is presented that sesquiterpene lactones or ketones containing the O=CC=CH2 moiety, e.g., tenulin and helenalin, alkylate the thiol group of reduced glutathione and L-cysteine in vitro. A proposal is offered that this mechanism of action is responsible for the observed potent in vivo antitumor activity of these agents in the Ehrlich ascites and Walker 256 carcinosarcoma and to a lesser extent in the P388 leukemic screen. Inhibition of tumor growth is thought to occur due to the O=CC=CH2 system alkylating by rapid Michael addition the SH biological nucleophiles of key regulatory enzymes of nucleic acid and chromatin metabolism. This proposition is in accord with the ability of these agents to inhibit DNA synthesis and gene activity of Ehrlich ascites cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Ascitic Fluid; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Chromatin; Cyclopentanes; Cysteine; DNA, Neoplasm; Glutathione; Histidine; Lactones; Leukemia, Experimental; Leukemia, Lymphoid; Male; Mice; Mice, Inbred DBA; Neoplasm Proteins; Rats; Sesquiterpenes; Sesquiterpenes, Guaiane; Spectrophotometry, Ultraviolet; Time Factors

The differential distribution of a series of antineoplastic agents in metastatic tissues compared to their respective primary tumors has been investigated in one rat and two mouse experimental tumor systems, ie, the intramuscular Lewis lung carcinoma (3LL) of C57BL/6 mice, which gives rise to spontaneous lung metastases, the intratibial Sarcoma 180 (S180) of CD1 mice, which induces macroscopic metastases to the lymph nodes, and the Walker 256 carcinosarcoma of CD rats, which also metastasizes to the lymph nodes. The results described in this paper show that the concentrations of adriamycin, daunorubicin, cyclophosphamide and its alkylating metabolites, hydroxyurea, 1-methyl-1-nitrosourea, and 6-mercaptopurine are much higher in the pulmonary metastases of 3LL and/or in the lymph node metastases of S180 than the concentrations measured in the primary tumor. In the Walker 256 tumor system the distribution of adriamycin appears to follow the same pattern observed for the mouse tumors. Only for methotrexate (in the 3LL tumor) is the difference in the concentrations at the two sites not so evident. These findings are discussed in relation to the comparatively greater sensitivity of metastases to chemotherapy.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Carcinoma 256, Walker; Cyclophosphamide; Daunorubicin; Doxorubicin; Female; Hydroxyurea; Lung Neoplasms; Lymphatic Metastasis; Male; Mercaptopurine; Methotrexate; Methylnitrosourea; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Rats; Sarcoma, Experimental

Topics: Animals; Carcinoma 256, Walker; Cyclophosphamide; Kinetics; Liver; Male; Mercaptopurine; Neoplasm Transplantation; Neoplasms; Perfusion; Rats; Transplantation, Homologous

Topics: Alkylating Agents; Animals; Antibiotics, Antineoplastic; Ascites; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Drug Resistance; Leukemia L1210; Leukemia, Experimental; Mercaptopurine; Methotrexate; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Piperazines; Piperidines; Transplantation, Homologous

Topics: Adenosine; Animals; Benzene Derivatives; Carcinoma 256, Walker; Cell Division; Cells, Cultured; Drug Synergism; Evaluation Studies as Topic; Leukemia L1210; Mercaptopurine; Mice; Mice, Inbred DBA; Rats; Sarcoma 180; Thioguanine

Topics: Alkylation; Animals; Azaguanine; Binding, Competitive; Carcinoma 256, Walker; Cyclophosphamide; Desoxycorticosterone; Dose-Response Relationship, Drug; Female; Gonadal Steroid Hormones; Male; Meperidine; Mercaptopurine; Metyrapone; Microsomes, Liver; Morphine; Phenacetin; Proadifen; Probenecid; Quinine; Rats

Topics: Animals; Ascites; Body Weight; Carcinoma; Carcinoma 256, Walker; Coenzymes; Female; Half-Life; Liver; Lung; Male; Mercaptopurine; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Sarcoma; Spleen; Time Factors; Transplantation, Homologous

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carcinoma 256, Walker; Dactinomycin; Fluorouracil; Melphalan; Mercaptopurine; Methylthiouracil; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Nitrogen Mustard Compounds; Rats; Sarcoma, Experimental; Time Factors

Topics: Adenocarcinoma; Animals; Carcinoma 256, Walker; Chlorambucil; Cyclophosphamide; Melphalan; Mercaptopurine; Mice; Neoplasms, Experimental; Sarcoma, Experimental

Topics: Animals; Carcinoma 256, Walker; Female; Immune Sera; Immunization; Liver; Mercaptopurine; Mice; Pyridoxine; Sarcoma 180; Spleen; Thiosemicarbazones; Thymus Gland

Topics: Animals; Antibody Formation; Antigen-Antibody Reactions; Carcinoma 256, Walker; Cyclophosphamide; Cytarabine; Endotoxins; Floxuridine; gamma-Globulins; Injections; Mercaptopurine; Mice; Rats; Thiosemicarbazones; Uracil Mustard