Inhibition by alkyl-lysophospholipids of tritiated thymidine uptake in cells of human malignant urologic tumors.

Alkyl-lysophospholipids (ALP) inhibited the uptake of [3H]thymidine by cells from a variety of human urologic tumors in vitro. Cells of prostate carcinomas, a seminoma, various bladder carcinomas and teratocarcinomas showed proliferation rates that were 10% of those of the controls when incubated with some ALP for longer than 24 hours. Concentrations as low as 1 microgram ALP/ml medium (10(6) tumor cells) were effective. Antitumor action increased after incubation for 2-5 days. Morphologic studies showed tumor cell death after incubation periods of this length. Equivalent concentrations of conventional cytostatic drugs used in anticancer chemotherapy protocols did not cause greater inhibition of [3H]thymidine uptake by tumor cells in vitro. Human embryonic fibroblasts were not sensitive to ALP, whereas cytostatic drugs completely inhibited their proliferation at comparable doses.

Removal of breast cancer cells from bone marrow by in vitro purging with ether lipids and cryopreservation.

Four cell lines from human breast cancer (HTB 19, HTB 133, IZB B, and MCF 7M) were investigated for in vitro growth before and after incubation with the ether lipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) for 4 h and at increasing concentrations (25, 50, 75, and 100 micrograms/ml), as well as with and without cryopreservation. When measured with the human tumor cloning assay in agar or methyl-cellulose the surviving fraction showed an inverse correlation with the concentrations of ET-18-OCH3. After a 4-h exposure with 75 micrograms/ml ET-18-OCH3 at a cell density of 2 x 10(5)/ml the number of colonies of HTB 19 decreased from 75 +/- 10/10(3) cells (100%) to 1 +/- 0/10(3) cells (1%), and after subsequent cryopreservation no remaining colonies were found. In order to simulate the situation in autologous bone marrow transplantation we contaminated normal human bone marrow cells with malignant HTB 19 breast cancer cells at a ratio of 100:1. After incubation with 75 micrograms/ml ET-18-OCH3 for 4 h and subsequent cryopreservation there was a considerable reduction of HTB 19 colonies whereas the majority of normal human hematopoietic progenitors recovered. We conclude that ET-18-OCH3, in combination with cryopreservation, can remove breast cancer cells from bone marrow by up to 1 log and may be useful for purging bone marrow for autologous bone marrow transplantation not only in acute leukemia and non-Hodgkin's lymphoma but also in breast cancer.

Cytotoxicity of thioether-lysophospholipids in leukemias and tumors of human origin.

Thioether-lysophospholipids inhibited the in vitro incorporation of [3H]thymidine into blasts of 8 leukemias, lymphocytes of 3 chronic lymphocytic leukemias, and cells of 12 different solid tumors of human origin. This effect correlated with trypan blue dye exclusion, which was used to assess cell damage. Scanning electron microscopy revealed severe membrane destruction after incubation with thioether-lysophospholipids. Cytostatic and cytotoxic effects of thioether-lysophospholipids were dependent on dosage and incubation time. Destruction of leukemic blasts was completed with greater than or equal to 5 micrograms/ml after an incubation of greater than or equal to 48 hr, but 10 to 20 micrograms/ml were necessary in solid tumors. Ester-linked 2-lysophosphatidylcholine was ineffective in the same dose range, which points to the requirement of the alkyl moiety in SN1 of the molecule for the antineoplastic properties of lysophospholipid analogues.

Cytotoxicity of the alkyl-linked lipoidal amine 4-aminomethyl-1-[2,3-(di-n-decyloxy)-n-propyl]-4-phenylpiperidine (CP-46,665) in cells from human tumors and leukemias.

The alkyl-linked lipoidal amine 4-aminomethyl-1-[2,3-(di-n-decyloxy)-n-propyl]-4-phenylpiperidine (CP-46,665) inhibited the in vitro incorporation of tritiated thymidine into blasts of eight leukemias and cells of nine different solid tumors of human origin. This activity was well correlated with trypan blue dye exclusion, which was tested to assess cell membrane damage. Scanning electron microscopy revealed loss of cell surface features and severe cell membrane destruction after incubation with CP-46,665. These effects on thymidine uptake and single cell viability were accompanied by a clear loss of the reproductive capacities of human tumor and leukemic cells as measured in a human tumor stem cell assay after incubation with CP-46,665. The above-mentioned cytostatic and cytotoxic effects of CP-46,665 were dependent on dosage and incubation time. Destruction of leukemic blasts was often completed with greater than or equal to 5 micrograms/ml after an incubation of greater than or equal to 48 hr or greater than or equal to 10 micrograms/ml after an incubation of greater than or equal to 24 hr. Cells from solid tumors usually required a slightly higher drug concentration and longer incubation period for maximum killing. The alkyl-linked lipoidal amine CP-46,665 often showed considerably greater efficacy than did the alkyl-linked phospholipid rac-1-O-octadecyl-2-O-methylglycero-3-phosphocholine tested in comparison. In contrast to both drugs, 2-lysophosphatidylcholine showed only minor activity within the same dose range.

Some antagonists of platelet activating factor are cytotoxic for human malignant cell lines.

Nine new platelet activating factor (PAF) antagonists from 4 different chemical classes (thiopyrimidines: SDZ 59-015; thioimidazolines: SDZ 61-813; imidazoisoquinolines: SDZ 62-434, SDZ 62-759, SDZ 63-135, SDZ 63-596; and imidazopiperidines: SDZ 61-638, SDZ 62-293, SDZ 62-694) have been tested for cytostatic/antiproliferative ([3H]thymidine uptake) and cytotoxic (trypan blue dye exclusion) activity in neoplastic human cell lines of different histology in vitro. The antiproliferative activity of 3 of the 9 PAF antagonists (SDZ 61-638, SDZ 61-813, SDZ 62-694) was not stable after freezing and thawing. SDZ 59-015 showed only minor cytotoxic or antiproliferative effects in a dose range of 2-40 microns after 24, 48, and 72 h of incubation. SDZ 62-434 showed varying activity. There were no significant differences between the activities of the other 3 PAF antagonists from the imidazoisoquinoline class, which showed drug concentrations inhibiting 50% of the activity studied (IC50) and drug concentrations yielding a 50% decrease of trypan blue dye exclusion (LC50) of less than or equal to 20 microM at greater than or equal to 48 h, even in the K-562 cell line, which is known to be rather resistant for a variety of cytotoxic drugs related to PAF. SDZ 62-293 showed the best antineoplastic properties with IC50 and LC50 values less than or equal to 10 microM at greater than or equal to 48 h including K-562. SDZ 62-434, SDZ 62-759, SDZ 63-135, SDZ 63-596, and SDZ 62-293 have been further tested in a human tumor cloning assay in 5 cell lines. Colony formation was reproducibly suppressed to less than 30% of the controls only by SDZ 63-135 (less than or equal to 40 microM) and SDZ 62-293 (less than or equal to 20 microM) during continuous exposure. There was no correlation between the IC50 values for the antiproliferative activity of the test compounds and their IC50 values for PAF-induced human platelet aggregation. Furthermore, the antiproliferative activity of the most active compound, SDZ 62-293, could not be antagonized by preincubation with the specific PAF antagonists WEB 2170 or WEB 2086 or PAF itself in noncytotoxic doses.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of 1-beta-D-arabinofuranosylcytosine conjugates of lipids on the growth and metastasis of Lewis lung carcinoma.

Five different lipid conjugates of 1-beta-D-arabinofuranosylcytosine (ara-C) were tested for their therapeutic activity on the growth and metastasis of Lewis lung carcinoma (3-LL). Among 1 ester-linked lipid conjugate (Ara-CDP-L-dipalmitin), 3 1-O-alkyl-lipid conjugates (ara-CDP-D,L-PBA, ara-CDP-D,L-PCA, ara-CDP-D,L-MBA) and a thioether-lipid conjugate (ara-CDP-D,L-PTBA) ara-CDP-D,L-PTBA, ara-CDP-D,L-PBA, and ara-CDP-L-dipalmitin produced the strongest tumor growth inhibition and increase of surviving animals in C57Bl6-mice bearing i.p.-implanted 3-LL. Furthermore these conjugates were superior to the parent compounds alone, or equimolar mixtures of the alkyllysophospholipid derivatives ET-18-OCH3 and ara-C. Successful therapeutic regimen consisted of 80-100 mg conjugate/kg, given i.p. daily for five consecutive days. Similar regimen injected shortly after the surgical removal of the primary tumor as adjuvant chemotherapy inhibited the metastasis of 3-LL to the lungs of the animals as demonstrated by an increase of survival time and the number of surviving animals.

Cytotoxicity of alkyl-lysophospholipid derivatives and low-alkyl-cleavage enzyme activities in rat brain tumor cells.

Alkyl-lysophospholipids (ALP) and related derivatives inhibited the in vitro incorporation of [3H]thymidine into seven different permanent cell lines derived from rat brain tumors. The cytostatic effect of ALP was dependent on dosage and incubation time. Naturally occurring 2-lysophosphatidylcholine did not exhibit cytostatic effects; under these conditions, the incorporation rates of [3H]thymidine were generally more than 100% of the controls. The trypan blue dye exclusion test, which was used to assess severe cell damage, correlated with the extent that [3H]thymidine incorporation was inhibited by ALP. Preincubation of ALP (rac-1-octadecyl-lyso-glycero-3-phosphocholine) for more than 8 min with a tetrahydropteridine-dependent O-alkyl cleavage enzyme preparation from rat liver microsomes destroyed almost all of the cytotoxic properties of ALP when tested at a concentration that previously inhibited tumor growth by more than 50%. [3H]Thymidine incorporation rates were greater than 100% for astrocytoma cells incubated with ALP after exposure to the alkyl cleavage enzyme. Comparison of the microsomal activities of the tetrahydropteridine-dependent alkyl-cleavage enzyme present in astrocytoma 78-FR-G-299 cells and the pleomorphic glioma 78-FR-G-219/S4 cells to that found in normal skin fibroblasts and rat livers revealed a markedly reduced activity in the neoplastic cell lines. Moreover, those tumor cells that were more resistant to ALP cytotoxicity (pleomorphic glioma, 78-FR-G-219/S4) had a 3-fold higher tetrahydropteridine-dependent cleavage activity than a more cytotoxic sensitive line (astrocytoma cells, 78-FR-G-299). Our results indicate that the low-alkyl-cleavage enzyme activities in these neoplastic cells in comparison to normal cells might be a factor in explaining the relatively high cytotoxicity of ALP in tumor cells.

Different susceptibility of protein synthesis to inhibitors of elongation in cell-free systems from plasma cell tumours and reticulocytes.

Plasma cells and reticulocytes are mammalian cell systems which have specialized in the synthesis of a single protein during their differentiation from one common stem cell. To study whether there is a difference in cell susceptibility at the level of elongation, dose vs. inhibition curves of sparsomycin, cycloheximide and emetine in cell-free systems with S-30 fractions from plasma cell tumours (MOPC 63, MOPC 41, RPC 20, MOPC 104 E), reticulocytes and liver were compared. The experiments revealed: (1) all the selected systems are equally sensitive to sparsomycin; (2) the susceptibility of the reticulocyte systems to cycloheximide and emetine is higher than that of the plasma cell tumours. In the dose range of 1 - 10(-7) --5 - 10(-5) M cycloheximide and 1 - 10(-6)--1 - 10(-4) M emetine the reticulocyte system is preferentially inhibited; (3) the sensitivities of all plasma cell tumours are equal; (4) the liver system is more sensitive to emetine than to cycloheximide; (5) the site of the different susceptibility to these antibiotics could be located on the ribosomes; (6) however, when the extracts of the plasma cell tumours were prepared in the presence of hemin, their susceptibility rises and is like that of reticulocytes. These results show that hemin promotes in a cell-specific manner the sensitivity to some inhibitors of protein synthesis.

Differential cytotoxicity of an ether lipid on lymphoma and bone marrow cells and its role in purging malignant lymphoid cells from remission bone marrow contaminated with tumor cells.

Four human clonogenic malignant lymphoid cell lines (CEM, Su-DHL-4, Li-A, and Raji) as well as normal human bone marrow stem cell progenitor cells were investigated for clonal in vitro growth before and after incubation with the ether lipid ET-18-OCH3 for various times (1, 4, and 18 h) and at increasing concentrations of the drug (25, 50, 75, and 100 micrograms/ml). The clonal growth of the malignant lymphoid cell lines was inversely correlated with concentrations and times of drug incubation. The antineoplastic effect of ET-18-OCH3 was further amplified by subsequent cryopreservation. In a situation of 4-h exposure to less than or equal to 50 micrograms/ml ET-18-OCH3 and subsequent cryopreservation, in which greater than 50% of the normal human bone marrow progenitor cells survived, 1-3 logs of the malignant lymphoblastoid cells were killed, indicating a potential value of this drug for bone marrow purging in lymphoid malignancy. In order to simulate the situation of autologous bone marrow transplantation (ABMT) in complete remission of the disease, we contaminated normal human bone marrow cells with malignant CEM or Su-DHL-4 lymphoid cells at a ratio of 100:1. Results show that 4 h of incubation with 75 micrograms/ml ET-18-OCH3 and subsequent cryopreservation can eliminate 2-3 logs of clonogenic cells of the malignant lymphoblastoid cell lines under conditions that allow recovery of greater than 50% of the normal human hematopoietic progenitors.

Therapeutic activity of 1-beta-D-arabinofuranosylcytosine conjugates of lipids in WEHI-3B leukemia in mice.

Two new conjugates of 1-beta-D-arabinofuranosylcytosine (ara-C) and lipids were tested for therapeutic activity in myelomonocytic WEHI-3B leukemia in mice. Both conjugates were superior to equimolar mixtures of their respective parent compounds and to ara-C alone. IP treatment was found effective after either IP or IV transplantation of the leukemia. The thioether-linked lipid conjugate ara-CDP-D,L-PTBA showed considerably higher efficacy than the ester-linked lipid conjugate ara-CDP-L-dipalmitin. The optimal therapeutic regimen of ara-CDP-D,L-PTBA consisted of 60 mg/kg given IP qd 1-5 after transplantation of the WEHI-3B leukemia.

Effects of the microtubule-disturbing agents docetaxel (Taxotere), vinblastine and vincristine on epidermal growth factor-receptor binding of human breast cancer cell lines in vitro.

Epidermal growth factor (EGF) is a mitogenic peptide that binds to surface membrane receptors (EGFR) of breast cancer cells. After binding, secondary transmitter molecules are activated by tyrosine phosphorylation of the intracellular receptor domaine. The activity of the EGF/EGFR system can be modulated by a variety of chemically unrelated compounds including cytostatic agents. The purpose of our present study was to determine the effects of mitotic inhibitors on EGF receptor binding on human breast cancer cells. We found that MDA-231 and MDA-468 cells bind substantially more [125I]EGF after preincubation with docetaxel, vinblastine and vincristine. This effect was concentration- and time-dependent, reaching a maximum at 3000 ng/ml and 48 h incubation for docetaxel, and 100 ng/ml and 48 h incubation for vinca alcaloids. Subsequent experiments showed an increase in the rate of EGF binding as well as maximal binding capacity. Scatchard analysis of binding experiments under equilibrium conditions indicated that this was due to an increase in the number of apparent EGF binding sites. Modulation of EGF receptor binding by docetaxel, vinblastine, and vincristine was not detectable when isolated membranes were used, indicating that intact cytoplasmatic mechanisms are required for the upregulation of EGF receptors.

Activity of NK 611, a new epipodophyllotoxin derivative, against colony forming units from freshly explanted human tumours in vitro.

NK 611 is a new semisynthetic analogue of etoposide, which presumably also acts through inhibition of topoisomerase II, and has been found to be more potent against several cancer cell lines in vitro than etoposide. The objectives of our study were to determine the activity of NK 611 against freshly explanted clonogenic cells from human tumours and compare this agent with etoposide and other clinically useful agents. After exposure for 1 h in 45 evaluable tumour specimens, NK 611 showed clear concentration-dependent antitumour activity. At 51 microM, 49% of specimens were markedly inhibited. Using a long-term (21-28 day) exposure at 6.8 microM, 58% of 50 evaluable specimens were profoundly inhibited. At equimolar concentrations, NK 611 was as active as etoposide. Across all tumour types studied, NK 611 was as active as vinblastine, bleomycin, doxorubicin, 5-fluorouracil, mitomycin-C and cisplatin. Our results showed cross resistance to etoposide in the majority of specimens. Activity of NK 611 was greater with long-term exposure than with short-term exposure indicating schedule dependency. We conclude that NK 611 has a wide spectrum of in vitro antitumour activity. Since preliminary clinical information suggests that this drug is well tolerated at high doses, further development of this agent in Phase II trials with multiple dosing schedules is warranted.

Preclinical activity of taxotere (RP 56976, NSC 628503) against freshly explanted clonogenic human tumour cells: comparison with taxol and conventional antineoplastic agents.

Taxotere (TER) and taxol (TA) are new antitumour agents currently undergoing clinical evaluation. We studied the antineoplastic effects of these agents (final concentrations: 4.0, 0.4, 0.04 mumol/l) on the in vitro proliferation of clonogenic cells from freshly explanted human tumours using a capillary soft agar cloning system. We also compared the activity of these new compounds to conventional antineoplastic agents (bleomycin, cisplatin, dacarbazine, doxorubicin, etoposide, 5-fluorouracil, vinblastine, interferon-alpha 2). Using a 21-28-day continuous drug exposure, 54/81 specimens (67%) were evaluable for comparisons, and using a 1-h drug exposure followed by 21-28 days incubation, 50/80 specimens (63%) were similarly evaluable. With both schedules, TA and TER showed concentration-related antitumour activity. At 0.4 mumol/l, median colony survival was 0.61 x control (range 0.09-0.96) for TA and 0.51 x control (0.15-0.81) for TER in the 1-h incubation (P = 0.0002). Median colony formation was also reduced significantly more by TER as compared to TA in the long-term incubation schedule. Statistical analysis indicated that TER but not TA was significantly more active than cisplatin (P = 0.02), doxorubicin (P = 0.01), 5-fluorouracil (P = 0.01) and interferon-alpha 2 (P = 0.01). We conclude that TER and TA are more active against in vitro tumour colony formation from freshly explanted human tumours. TER appears to be slightly more active than taxol and promises to be active against tumours resistant to conventional antineoplastics.

Preclinical activity of trans-indazolium[tetrachlorobisindazoleruthenate(III)] (NSC 666158; IndCR; KP 1019) against tumour colony-forming units and haematopoietic progenitor cells.

Trans-indazolium[tetrachlorobisindazoleruthenate(III)] (KP 1019) is a new heavy metal complex with promising activity against tumour cell lines and in animal models. We studied the antineoplastic effects of KP 1019 (final concentrations: 1, 10, 100 micrograms/ml) on in vitro proliferation of clonogenic cells from freshly explanted human tumours in a capillary soft agar cloning system, and compared the activity of KP 1019 with conventional antineoplastic agents. 53 of 75 specimens (71%) showed adequate growth in controls. KP 1019 inhibited tumour colony formation in a concentration-dependent manner in both short- (1 h) and long-term (21 d) exposure experiments. KP 1019 at 100 micrograms/ml with 1 h exposure was as active as bleomycin, cisplatin, doxorubicin, etoposide, 5-fluorouracil, methotrexate, mitomycin-C and vinblastine, with only paclitaxel more active than KP 1019 (P = 0.002). The antitumour activity of KP 1019 was more pronounced after long-term exposure, indicating the potential schedule dependency of KP 1019. Activity was observed against non-small cell lung, breast and renal cancer. We conclude that if appropriate plasma levels can be achieved in patients, KP 1019 may have significant clinical activity against a variety of different tumour types.

Gemcitabine and etoposide in small cell lung cancer: phase I and II trials.

Gemcitabine and etoposide have both shown single-agent activity against multiple tumor types in clinical trials, including small cell lung cancer, but have not been previously used together. Forty-four patients with small cell and non-small cell lung cancer or other tumor types were enrolled in a phase I dose-finding trial using this drug combination. Gemcitabine 1,000 mg/m2 was given intravenously on days 1, 8, and 15 of a 28-day cycle, and etoposide (dose escalated from 20 to 80 mg/m2) was given on days 8, 9, and 10. Leukopenia, thrombocytopenia, and anemia were the major toxicities noted. Objective responses were observed in five of 44 patients. The maximum tolerated dose of etoposide was determined to be 80 mg/m2. On the basis of these results, a phase II trial of gemcitabine and etoposide in patients with small cell lung cancer has been initiated. Twelve patients have been enrolled in this ongoing trial, and toxicity to date has been manageable.

Clinical phase I study of paclitaxel followed by cisplatin in advanced head and neck squamous cell carcinoma.

We performed a clinical phase I trial of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, using a 3-hour infusion of paclitaxel followed by a 1-hour infusion of cisplatin. Treatment with this combination was repeated every 21 days. Patients who had received prior treatment with platinum-containing regimens were excluded. However, patients who had received two or fewer courses of radiochemotherapy not including platinum compounds were eligible. At present, 21 patients have been entered into this ongoing study. Doses ranged from paclitaxel 135 mg/m2 plus cisplatin 75 mg/m2 to paclitaxel 250 mg/m2 plus cisplatin 100 mg/m2. The maximum tolerated dose was reached at paclitaxel 250 mg/m2 and cisplatin 100 mg/m2. The dose-limiting toxicity of this regimen was myelosuppression (leukopenia, granulocytopenia). Clinically, neurosensory toxicity was moderate. However, preliminary analyses of threshold electrotonus studies indicate the presence of subclinical neurotoxicity in most patients. One patient receiving paclitaxel 200 mg/m2 plus cisplatin 100 mg/m2 developed grade 3 motor neurotoxicity. Profound orthostatic hypotension was observed in five patients receiving paclitaxel 200 mg/m2 plus cisplatin 100 mg/m2 or higher. Neurotoxicity was of delayed onset and slowly reversible, and its severity appeared to be dose related. Twelve patients are currently evaluable for response. Of these, three partial remissions were observed (6, 6+, and 3+ months). Five additional patients had stable disease. We conclude that the combination of paclitaxel administered as a 3-hour infusion followed by cisplatin is an active regimen in advanced head and neck cancer. In addition to myelosuppression, orthostatic hypotension may be a potentially significant clinical toxicity. Clinical phase II studies have been initiated, using a dose of paclitaxel 200 mg/m2 and cisplatin 100 mg/m2.

Alkyl-lysophospholipids lack influence on the occurrence of radiation-induced lymphomas and AKR-leukemia.

Oral application of 2 synthetic alkyl-lysophospholipids ET-18-OCH3 and ET-18-OH at 50 micrograms/mouse every second day during the time to detect the appearance of tumors did not prevent or delay the occurrence of radiation-induced lymphomas or AKR-leukemia in mice.

Lack of therapeutic activity of the lipoidal amine CP-46,665 in rodent tumors and human non-seminomatous germ cell tumors growing in nude mice.

The alkyl-linked lipoidal amine 4-aminomethyl-1-[2,3-(di-n-decyloxy)-n-propyl]-4-phenylpiperidine (CP-46,665) was tested for therapeutic activity in 2 rodent tumor models and 2 human non-seminomatous germ cell tumors growing in nude mice. CP-46,665 failed to show therapeutic efficacy in 3-Lewis lung carcinoma (3-LL) growing in syngeneic C57Bl6-mice, in methylnitrosourea (MNU)-induced rat mammary carcinomas and in 2 human non-seminomatous germ cell tumor cell lines (H 12.1, H 12.7) growing in nu/nu NMRI-mice when given in a dose range including non-toxic doses and doses higher than the lethal dose for 10% of the treated animals (LD10).

Antitumoral activity of a xanthate compound. I. Cytotoxicity studies with neoplastic cell lines in vitro.

Xanthate derivatives were shown previously to display antitumor activity against transformed fibroblasts and lymphoma cells in combination with monocarboxylic acids [1]. Various malignant cell lines of human origin were treated in vitro to explore the range of antitumoral activity of the compounds. The combination of tricyclodecan-9-yl-xanthogenate (D 609) with undecanoic acid (C11) exerted dose dependent cytotoxic and antiproliferative effects on cell lines both from solid tumors (glioblastomas, colon-carcinomas) and hematological diseases (lymphomas, CML/BC). Additionally, the combination of D 609/C11 was able to kill both methotrexate- and adriamycin-resistant L 1210 and S 180 cells, indicating that there is no cross-resistance for these drugs and D 609/C11 in vitro.

Antitumoral activity of a xanthate compound. II. Therapeutic studies in murine leukemia and tumor models in vivo.

The combinations of tricyclodecan-9-yl-xanthogenate (D 609) with undecanoic acid (C11) and D 609 with myristic acid (C14) were tested in 3 rodent tumor models in vivo. D 609 in combination with C11 or C14 did not show antitumoral efficacy in 3-Lewis lung carcinoma (3-LL) growing in syngeneic C57BL6-mice (primary tumor and metastasis) or in WEHI-3B myelomonocytic leukemia growing in Balb/c mice, when given in a dose range lower than the lethal dose for 10% of the treated animals (LD10). In L 1210 mouse lymphoid leukemia growing in CD2F1 mice the combination of D 609/C11 given intraperitoneally in a concentration of 100 mg/kg for more than 1 day effected a significant difference in the survival curves between the control and therapeutic groups in 1 out of 2 experiments. In conclusion, the treatment schedules of D 609/C11 or D 609/C14 used in this study has not revealed significant therapeutic effects in mouse tumors or leukemias in vivo.