mercaptopurine and Fibrosarcoma

In addition to the known sodium 3,7,11,15-tetramethylhexadeca-1,19-diyl sulfate (4), the BuOH extract of the Mediterranean tunicate Sidnyum turbinatum was shown to contain four new metabolites: 1-heptadecanyl sulfate (1), 1-octadecanyl sulfate (2), sodium (2S)-2,6,10,14-tetramethylpentadeca-1,18-diyl sulfate (3), and 1-hexyl sulfate (5). Their structures were determined by spectroscopic and chemical methods. Compounds 1-5 exhibited in vitro antiproliferative activity estimated on the WEHI 164 cell line.

Topics: Animals; Cell Division; Drug Screening Assays, Antitumor; Fibrosarcoma; Magnetic Resonance Spectroscopy; Mercaptopurine; Mice; Models, Chemical; Spectrometry, Mass, Fast Atom Bombardment; Sulfates; Tumor Cells, Cultured; Urochordata

We investigated possible mechanisms of the antitumor action of gamma-(9H-purine-6-yl) thiomethyl L-glutamate (6-MPG), a water-soluble derivative of 6-MP. In the double grafted tumor system, BALB/c mice were inoculated intradermally with 10(6) cells of MethA fibrosarcoma at the right inguinal region on day 0 (the primary tumor) and later with 3 x 10(6) cells at the left on day 10 (the secondary tumor). Intraperitoneal administration of 6-MPG at a dose of 100 mg/kg/day from day 3 through 7 completely prevented growth of the secondary tumor. 6-MPG showed no effect on growth of colon 26 adenocarcinoma cells inoculated in place of the secondary MethA cells (antigen specificity). 6-MPG did not inhibit the secondary MethA growth in the BALB/c (nu/nu) mouse. The inhibitory effect of 6-MPG on the secondary tumor growth was diminished by prior treatment of the primed animals with cyclosporin A and anti-Thy antibody. Spleen cells from the tumor-bearing mice treated with 6-MPG showed a tumor-neutralizing activity (Winn assay). Treatment of the spleen cells with anti-CD8 antibody plus complement diminished the tumor-neutralizing effect but that with anti-CD4 antibody plus complement did not, indicating that CD8-positive cells are responsible for potentiation of the tumor immunity. These results suggest that the antitumor effect of 6-MPG against the secondary tumor is elicited by augmenting tumor specific T-cell production.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Animals; Antineoplastic Agents; Cell Division; Colonic Neoplasms; Cyclosporine; Drug Interactions; Fibrosarcoma; Immunosuppressive Agents; Male; Mercaptopurine; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Phenotype; Solubility; Spleen; T-Lymphocytes; Water

Inhibitory effects on some immunological responses and MethA fibrosarcoma in the double grafted tumor system in mice were compared between 6-mercaptopurine (6-MP) and its novel water-soluble derivative, gamma-(9H-purine-6-yl)thiomethyl L-glutamate (6-MPG). The dose-dependent inhibitory effects by 6-MPG on the hemagglutinin response to SRBC, DTH reaction to MBSA, contact sensitivity to oxazolone, GVH response and growth of the primary tumor were 3-10 times weaker than those by 6-MP, probably reflecting the difference in their cytotoxicities antimetabolites. However, the two drugs were nearly equipotent in reproducing inhibition of the secondary tumor growth, which is a host-mediated immunological response to tumor antigen as shown by its dependency on the primary inoculation with 1 x 10(4) or more MethA cells and by the production of anti-tumor splenocytes in tumor-bearing animals (the Winn assay). Thus, 6-MPG may point to the direction of derivatization towards anti-tumor immunopotentiators with an improved therapeutic index.

Topics: Adjuvants, Immunologic; Adoptive Transfer; Animals; Cell Division; Fibrosarcoma; Hemagglutination; Male; Mercaptopurine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Transplantation; Sarcoma, Experimental; Solubility; Spleen

In an attempt to improve the effectiveness and bioavailability of 6-mercaptopurine, various kinds of water-soluble analogues, such as 6-S-aminoacyloxymethyl mercaptopurine derivatives (3a--m) and 6-S,9-disubstituted derivates (7a,b and 9a,b), were synthesized. These compounds were evaluated for activity to augment antitumor immunity by using a double grated tumor system. Antitumor activities against solid tumors (sarcoma 180 and colon 26) were also evaluated. Many compounds exhibited potent activities in both test systems. In particular, the aminopropionate derivative (3a) and the L-glutamate derivative (3f) showed significant enhancement of antitumor immunity together with potent antitumor activities.

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Fibrosarcoma; Magnetic Resonance Spectroscopy; Mercaptopurine; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Sarcoma; Solubility; Water

We investigated the antitumor effect of 6-mercaptopurine (6-MP) and its analogs using the double grafted tumor technique. BALB/c mice were inoculated intradermally with MethA fibrosarcoma cells at the right inguinal region on day 0 (the primary tumor) and at the left on day 10 (the secondary tumor). Intraperitoneal or intra-lesional administration of 6-MP, 6-mercaptopurine riboside (6-MP-r) and 6-mercaptopurine riboside triacetate (6-MPRTA) from day 3 to 7 dose-dependently inhibited growth of the secondary tumor. Without the primary inoculation, 6-MP showed no effect on growth of the tumor inoculated on day 10, indicating that the antitumor effect of 6-MP could not be attributable to its direct antimetabolic or tumoricidal action only, and that the primary tumor inoculation is necessary for these compounds to inhibits growth of the challenging tumor. 6-MP did not inhibit the secondary MethA growth in the BALB/c (nu/nu) mouse. Both CD4+ and CD8+ T cells increased in the spleen of mice treated with 6-MP. Meanwhile, delayed-type hypersensitivity (DTH) reaction to the methylated bovine serum albumin (MBSA) antigen at the footpad was not augmented but inhibited by 6-MP-r and 6-MPRTA in both normal and tumor-bearing mice. Thus, the immunomodulatory activity of 6-MP could be observed in two opposite directions, augmentation of tumor immunity and inhibition of DTH to MBSA. This indicates that the immune mechanism and/or the type of effector cells induced in these two cell-mediated immune systems are different from each other.

Topics: Adjuvants, Immunologic; Animals; Antimetabolites, Antineoplastic; Drug Screening Assays, Antitumor; Fibrosarcoma; Hypersensitivity, Delayed; Immunity, Cellular; Injections, Intraperitoneal; Male; Mercaptopurine; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Spleen; T-Lymphocytes

Topics: Aldehydes; Amidines; Animals; Antineoplastic Agents; Cyclophosphamide; Evaluation Studies as Topic; Female; Fibrosarcoma; Formamides; Hydrazones; Male; Mercaptopurine; Neoplasm Transplantation; Neoplasms, Experimental; Nickel; Rats

Topics: Cobalt Isotopes; Fibrosarcoma; Humans; Male; Mercaptopurine; Methods; Methotrexate; Neoplasm Recurrence, Local; Thyroid Neoplasms; Tomography; Tracheal Neoplasms