Dietary docosahexaenoic acid levels influence the outcome of arabinosylcytosine chemotherapy in L1210 leukemic mice.

The purpose of this study was to investigate whether dietary supplementation with the n-3 fatty acid docosahexaenoic acid (DHA) in combination with arabinosylcytosine (AraC) chemotherapy could prolong the life expectancy of mice bearing L1210 leukemia. The four control diets included rodent chow, a diet containing 5% of a blended oil mimicking the fatty acid composition of rodent chow, and diets containing 5% or 10% fat with safflower oil as the main oil source. The two DHA-supplemented diets provided 1.5% or 3.5% DHA and 5% or 10% total fat, respectively. After tumor cell inoculation, mice were treated with AraC for 10 days. Mice fed the 5% safflower oil diet (30.1 -/+ 4.1 days), but not those fed the 10% safflower oil diet, survived longer than the chow-fed animals (22.1 -/+ 3.1 days, P = 0.05). The 1.5%-/+ DHA diet (average intake 1.8 g DHA/kg/day) was associated with a longer life span (33.3 -/+ 3.4 days, P < 0.01 vs. chow-fed) and no incidence of death due to drug toxicity. Further increasing DHA intake (4.5 g DHA/kg/day) resulted in shortened survival time (26.5 -/+ 2.0 days), increased circulating tumor cell burden, and lowered red blood cell concentrations. These data suggest that a modest level of dietary DHA or linoleic acid supplementation may improve the antineoplastic efficacy of AraC. However, overconsumption of DHA reverses the beneficial effect of DHA intake on drug sensitivity.

Antileukemic effects of recombinant human tumor necrosis factor alpha (rh-TNF alpha) with cyclophosphamide or methotrexate on leukemia L1210 and leukemia P388 in mice.

We investigated the influence of recombinant human tumor necrosis factor alpha (rh-TNF alpha) administered as a single agent or in combination with cyclophosphamide (CY) or methotrexate (MTX) on the survival time of mice inoculated with lymphoblastic leukemia L1210 or lymphatic leukemia P388. The median survival time of leukemia L1210 bearing mice treated with rh-TNF alpha at doses ranging from 200 to 275 g/kg in daily i.p. injections was longer than that of control animals. Groups of mice with leukemia L1210 receiving rh-TNF alpha combined with either MTX or CY lived longer than animals treated with these agents individually. We observed only slight prolongation of life of animals inoculated with this tumor and treated with rh-TNF alpha at dose of 800 micrograms/kg in four injections on 2, 4, 6 and 8 day of experiment, and no effect when rh-TNF alpha was administered at dose of 200 or 400 micrograms/kg at the same treatment regime. In contrast no significant differences in lifetime were obtained from either simultaneous or sequential treatment of mice bearing leukemia P388. Groups of mice with this tumor treated with rh-TNF alpha in conjunction with either MTX or CY lived longer than controls, or rh-TNF alpha singly treated mice, but their survivals were not significantly prolonged compared with mice receiving cytostatics alone.

[Neuroleukemia in mice with leukemia L1210 treated with methotrexate]. / Neiroleikoz u myshei s leikozom L1210, lechennykh metotreksatom.

Histological investigations were conducted in 33 methotrexate-treated mice with leukemia L1210. It has been found that in nonsuppressed systemic leukemia process the development and progressing of initial morphologic signs of neuroleukemia takes place as a result of perivascular growth of leukemic infiltrates from the bone marrow of the cranial and vertebral bones into the adjacent structures of the central nervous system.

[Effect of chloramphenicol on the toxic and therapeutic actions of cyclophosphane]. / Vliianie khloramfenikola na toksicheskoe i lechebnoe deistvie tsiklofosfana.

The effect of chloramphenicol on the toxic and therapeutic action of cyclophosphamide was studied on CBA and DBA male mice. The animals were intact or infected with L1210 leukemia. It was found that the use of chloramphenicol prolonged the life-span of the mice and/or increased the number of the survivals after exposure to the lethal doses of cyclophosphamide. It reduced leukopenia and almost completely protected the animals from macular canities developing after administration of cyclophosphamide. The therapeutic effect of cyclophosphamide did not change after the use of chloramphenicol. The mechanisms of the above diverse effects of chloramphenicol on the toxic and therapeutic action of cyclophosphamide and the possibility of the use of chloramphenicol for lowering the cyclophosphamide toxicity in treatment of oncological patients are discussed.

New derivatives of CNC-amino acids and -oligopeptides: experimental antitumor activity.

The experimental antitumor activity of a series of new nitrosoureas is described in which the chloroethylnitrosocarbamoyl (CNC) group is attached to different carrier molecules: amino acids and oligopeptides. Of a group of 10 CNC-amino acid amide derivatives the majority displayed high therapeutic activity in L 5222 leukemia. Some compounds, especially the proline and sarcosine derivatives, showed favorable therapeutic ratios; 12 CNC-oligopeptides displayed a more or less pronounced therapeutic activity in L 1210 leukemia. Compounds bearing a free carboxy group were less active than the corresponding unsubstituted or N-methyl substituted amides.

Mitogenic inhibition and effect on survival of mice bearing L1210 leukemia using a combination of dehydroascorbic acid and hydroxycobalamin.

The present study was designed to test the effect of a combination of dehydroascorbic acid (DHA) and hydroxycobalamin (vitamin B12) on the survival of mice bearing L1210 leukemia. Results showed a significant increase in survival of treated mice compared with controls (p less than or equal to 0.0001) (Student's t-test). This positive effect was significantly lost when DHA was substituted by ascorbic acid (AA) in the same experimental conditions. In vitro findings also revealed that the DHA-B12 combination specifically inhibited mitoses of L1210 cells while non-neoplastic L929 cells were not affected.

Effect of forphenicinol, a small molecular immunomodifier, in combination with cyclophosphamide on growth of and immunity to syngeneic murine tumors.

Forphenicinol (FPL) is a low molecular immunomodifier derived from forphenicine, a microbial product found by Umezawa and co-workers. We studied the antitumor effect of FPL, cyclophosphamide (CY), and the combination of the two on several syngeneic murine tumors. The tumors used were mammary carcinoma, L1210 leukemia, B16 melanoma, Lewis lung carcinoma, and glioblastoma. A single ip injection of CY on Day 1 followed by eight consecutive daily oral doses of FPL beginning 6 days after tumor inoculation showed strong cooperation in curing syngeneic mammary carcinoma inoculated intradermally in C3H/HeN mice, most mice being cured of the tumor by the combination therapy and subsequently having acquired strong specific immunity. Treatment with FPL alone (either pre- or post-treatment) also significantly inhibited the growth of the mammary tumor. FPL and CY also showed cooperation in inhibiting the growth of L1210 leukemia transplanted intradermally into CDF1 (BALB/c X DBA/2) mice and markedly prolonged the survival time but FPL treatment alone had no effect. The FPL-CY treatment also affected Lewis lung carcinoma and glioblastoma in syngeneic C57BL/6 mice and produced therapeutic synergism. FPL alone significantly inhibited the growth of B16 melanoma in C57BL/6 mice as well as the syngeneic mammary carcinoma in C3H/HeN mice. These findings suggest that oral administration of FPL in combination with chemotherapeutic agents can be used for treating cancer without causing toxicity, because of the synergistic efficacy of the combination.

Effect of thymidine on the toxicity and antitumor activity of ftorafur.

The effects of thymidine (TdR) on the toxicity and antitumor activity of ftorafur (FT), a 5-FU analog, were determined. The LD10 of FT was 130, 430, and 680 mg/kg, respectively, when FT was administered ip in the following treatment schedules: (a) daily for 9 days, (b) every 4th day for three treatments, and (c) 1 day only. When FT was administered simultaneously with 250 mg/kg of TdR, the LD10 was 13, 62, and 630 mg/kg in the respective treatment schedules. Lethargy was observed in mice when the daily dose of FT was greater than or equal to 150 mg/kg. FT alone was active (% treated/control [T/C] = 153) against ascites P388 murine leukemia only at high, single doses. Simultaneous administration of FT and 250 mg/kg of TdR at or below the LD10 dose of FT resulted in an increase in the antitumor activity to a % T/C of 217 (daily, Days 1-9) and 188 (daily, Days 1, 5, and 9). The activity of FT administered simultaneously with TdR on Day 1 only (%T/C = 142) was lower than that for FT alone. Using a treatment schedule of Days 1, 5, and 9, a TdR/FT mol ratio of greater than or equal to 2.0 seems necessary to achieve an increase in therapeutic value against P388 murine leukemia. This may explain the lack of increase in activity against P388 when 250 mg/kg of TdR was coadministered with FT on Day 1 only. FT alone or coadministered with 250 mg/kg of TdR was equally active against L1210 ascites tumor at doses up to the LD10 with daily treatments on Days 1, 5, and 9 and on Days 1-9; the doses of FT, however, were below those which cause lethargy.

Effect of ricin and abrin on survival of L1210 leukemic mice and on leukemic and normal bone-marrow cells.

The effect of ricin and abrin on the survival of mice treated with L1210 leukemic cells intraperitoneally or intravenously was studied. In mice given 1 X 10(5) L1210 leukemia cells intraperitoneally a single dose of ricin (2.1 microgram/kg) intraperitoneally gave the best results, an increased life span (ILS) of 59%. Abrin also increased the life span of such animals although to a lesser extent. The effect of ricin was superior to that of 5-fluorouracil, but inferior to that of adriamycin, which gave a maximum ILS of 280%. In mice given L1210 cells intravenously no increase in life span was obtained with ricin, abrin or adiramycin, whereas 5-fluorouracil gave an ILS of 40-50%. In spleen colony assays the differential effect of ricin and abrin on the proliferative capacity of normal hematopoietic and leukemic colony-forming cells in bone marrow was studied. The differential effect of ricin was as good as that of adriamycin and considerably better than that of 5-fluorouracil. Abrin had a much smaller effect than ricin on both normal and leukemic cells. The effect of abrin on the leukemic cells was too small to be of therapeutic value. The results warrant exploration of the use of ricin in the treatment of human leukemia.

Optimization of high-dose methotrexate with leucovorin rescue therapy in the L1210 leukemia and sarcoma 180 murine tumor models.

An analysis of dose and schedule dependence of calcium leucovorin rescue during high-dose methotrexate therapy of ascitic forms of l1210 leukemia and Sarcoma 180 is reported. Schedules with very delayed "low-dose" leucovorin rescue following lethal doses of methotrexate were highly effective in preventing toxicity and achieved a pronounced antitumor effect in both ascites tumor models. Best results were obtained on a schedule of methotrexate (400 mg/kg s.c.) followed 16 to 20 hr later by calcium leucovorin (12 mg/kg s.c.) given once every 2 hr for a total of 5 doses. Progressive increases in the calcium leucovorin dosage on any schedule reduced both toxicity and the antitumor effect of methotrexate in each model. Following a single course of therapy, essentially no toxicity was observed, and the antitumor effects were 2-fold (L1210 leukemia) and 4-fold (Sarcoma 180) greater than a single, maximally tolerated dose (24/kg s.c.) methotrexate alone. An increase in the methotrexate dosage to 800 mg/kg s.c. with or without an increase in calcium leucovorin dosages on the same schedule did not appreciably increase the antitumor effect observed. Two courses of high-dose methotrexate (400 mg/kg s.c.) with leucovorin rescue (24 mg/kg s.c. 16, 20, and 24 hr after drug) given with an 8-day interval between courses doubled the total antitumor effect in each model with no substantial increase in toxicity and gave long-term survivors with Sarcoma 180. The results, overall, are in close agreement with prior prediction for schedule and dose dependence made on the basis of related pharmacokinetic and biochemical studies in murine tumor models reported from this laboratory.