Human tumor models in the severe combined immune deficient (scid) mouse.

PURPOSE: To test a number of established human tumor cell lines and early passage breast cancer (UACC2150) and melanoma cells (UACC1273) for growth in the scid mouse and the tumors' response to conventional chemotherapeutic drugs. METHODS: Established melanoma (A375, C81-61), colon (SW480), lung (A549), lymphomoblastoid leukemia (LCL-B), promyelocytic leukemia (HL60), prostate (PC-3, DU145), and breast (MCF7) cell lines were injected at subcutaneous (s.c.), intraperitoneal (i.p.), or mammary fat pad (MFP) sites. Tumor volume growth curves and survival curves were established for the various tumor cell lines. Carmustine (BCNU), cisplatin (CDDP), cyclophosphamide (CPA), doxorubicin, dacarbazine (DTIC), tamoxifen and vincristine were injected s.c. or i.p.. The chemotherapeutic drug effects on tumor volumes and survival were determined. RESULTS: Tumor growth occurred with each cell type. After i.p. injection, 90% mortality occurred within 26 to 60 days except for the early passage melanoma cell line UACC1273 with which mortality occurred within approximately 90 days. In the MCF7 breast model, treatment with tamoxifen (P < 0.001) and CPA (P < 0.0001) resulted in significant tumor growth delay compared with control groups. BCNU and CDDP resulted in significant tumor growth delays relative to control in SW480 colon cancer (P < 0.0014) and A375 melanoma (P < 0.0001) models, respectively. CPA and doxorubicin improved survival in the HL60 leukemia model (P = 0.0018). CONCLUSIONS: These scid mouse human tumor models appear to reflect the clinical situation in that clinically active chemotherapeutic drugs are similarly active in the scid mouse models. Therefore, the scid mouse models may be useful for testing new chemotherapeutic agents against various human cancer types.

Suppression of human lymphoma development in the severe combined immune-deficient mouse by imexon therapy.

Severe combined immune-deficient (SCID) mice accept human cell xenografts. SCID mice inoculated intraperitoneally with human peripheral blood mononuclear cells (PBMCs) from EBV-seropositive donors develop a form of disseminated human large cell lymphoma similar to that seen in transplant recipients and AIDS patients. Imexon (4-imino-1,4-diazobicyclo-3.1.0-hexan-2-one), a cyanoziridine immunomodulator with a selective inhibitory effect on B cells, was tested for its effect on this lymphoma development. Imexon started 2 weeks after PBMC inoculation significantly reduced the number of animals with lymphoma and the number of lymphomas sites per animal. The lymphoma was widely metastatic in the control animals but limited to the peritoneal cavity in the treated animals. Morphological and molecular parameters were used to confirm the reduced takes in the treated animals. Imexon was not myelosuppressive as determined by measurement of white blood cell counts. Imexon did not significantly suppress human IgG levels in the animals' serum. The tumor growth and lethality of human B lymphoblastoid cell lines in SCID mice was also suppressed by imexon treatment. A relatively nontoxic class of drugs that can suppress the development and/or growth of EBV-related lymphoma should be explored with priority for potential use in patients at high risk of this type of lymphoma.

Dose response and timing effects in the therapy of the LP-BM5 murine retrovirus-induced lymphoproliferative immunodeficiency disease with diethyldithiocarbamate.

Diethyldithiocarbamate (DTC) was used to treat the murine, retrovirus-induced, immunodeficiency disease (MAIDS). Once-weekly treatment was not effective and 800 mg/kg was toxic. When 200, 400 and 600 mg/kg were given i.p., 5 days per week, starting either on the day of virus inoculation or 14 days later, a dose-response and time-response relationship was noted. Higher doses and a 2-week delayed onset of treatment were generally more effective in reducing the development of lymphadenopathy, hypergammaglobulinemia and in prolonging survival than treatment started on the day of virus inoculation. When treatment was delayed until 10 weeks after virus inoculation existing lymphadenopathy was abrogated (treated node area 0 mm2 compared to control 175 mm2, P < 0.0001) and survival was improved (treated 100% compared to control 12.5%, P < 0.0001). However, when therapy was stopped animals died at the same rate as the untreated controls. These data indicate that DTC is active in MAIDS in a dose-responsive and time-dependent manner.

Treatment of the murine, retrovirus-induced lymphoproliferative immunodeficiency disease (LP-BM5) in C57BL/10 mice with the immunomodulator Imexon.

Imexon (4-imino-1, 3-diazabicyclo-(3.1.0)-hexan-2-one) a cyanoaziridine compound was studied in the treatment of the murine retrovirus-induced immunodeficiency disease model of AIDS (LP-BM5, MAIDS). Imexon, in dose-dependent fashion, partially prevented the development of hypergammaglobulinemia and splenomegaly, and partially prevented the decline in the phytohemagglutinin-induced proliferative response of spleen lymphocytes when started 1 or 15 days after virus inoculation. There was a statistically significant reduction in these disease-associated manifestations. When animals were treated starting 78 or 92 days after virus inoculation, lymphadenopathy was completely abrogated and survival was significantly prolonged in a dose-responsive manner. Since Imexon and other cyanoaziridine compounds have been safely administered to humans, we suggest that this class of compounds be further investigated in both large animal models of HIV infection and in patients with HIV-induced disease.

Effective therapy of the LP-BM5 murine retrovirus-induced lymphoproliferative immunodeficiency disease with diethyldithiocarbamate.

The effects of therapy with the immunomodulator diethyldithiocarbamate (DTC) on the manifestation and natural history of LP-BM5 murine retrovirus infection in adult C57 Black 6 mice was investigated. DTC itself, had limited effects on the spleen weight, serum IgM, or mitogen responses of the non-virus-infected control mice when evaluated over a 9-week period. The virus inoculum administered was such that there was approximately a twofold increase in serum IgM and a halving of phytohemagglutinin (PHA) and lipopolysaccharide (LPS) responses in about two weeks and death of all animals by about 26 weeks postinfection. Doses of DTC of 20 and 200 mg/kg weekly or 5 days per week (intraperitoneally) in mice with LP-BM5 infection did not alter the manifestations or course of the disease. Doses of 400 or 600 mg/kg given 5 days per week, starting either 2 weeks before or the day of virus inoculation significantly reduced hypergammaglobulinemia, spleen weight, lymphadenopathy, and also prolonged survival. A dose of 400 mg/kg started 2 weeks after virus inoculation resulted in partial prevention of hypergammaglobulinemia, splenomegaly, and lymphadenopathy as well as 100% survival compared with 12.5% in non-drug-treated controls at 23 weeks after virus inoculation. The 9 surviving animals in the treated group were then allocated to continue treatment or stop treatment. In the animals without further treatment, lymphadenopathy and mortality occurred starting within 6 weeks after cessation of therapy while the animals with continued treatment remained in good condition for 40 weeks. There was only a very limited and transient effect of DTC therapy on the decline of the proliferative responses to phytohemagglutinin or lipopolysaccharide in any of the treated groups in the above described experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological activity of diethyldithiocarbamate (Ditiocarb, Imuthiol) in an animal model of retrovirus-induced immunodeficiency disease and in clinical trials in patients with HIV infection. The Ditiocarb Study Group.

Diethyldithiocarbamate (Ditiocarb) is a drug with diverse biological activities suggesting that it may have multiple, clinical uses. Thus, it is an inhibitor of such enzymes as cytochrome P450, it is a chelating agent for nickel and cadmium, it is a free-radical scavenger and finally, it is an immunomodulator. As such, it can restore the immune responses of immunosuppressed mice. In the murine retrovirus-induced immunodeficiency disease (LP-BM5 in C57 black 10 mice), it can prevent the development of disease when given from the day of virus inoculation until 2 weeks after virus inoculation. In addition, it can reverse disease manifestations including lymphadenopathy when started as late as 10 weeks after virus inoculation. Associated with these effects is a reduction in mortality from 100 percent to between 0 and 10 percent. When drug is stopped however, disease progression resumes. In man, Ditiocarb has been used in a series of open, non-randomized as well as randomized prospectively-controlled clinical trials in patients with HIV infection. Three randomized placebo-controlled studies have been conducted. In the largest of these, involving 389 patients, Ditiocarb was shown to be safe, non-toxic and effective. Thus, there was a 62 percent reduction in new opportunistic infections (OI) in all of the treated patients, a 50 percent reduction in ARC patients and an 82 percent reduction in AIDS patients. When new and recurrent OI and other events indicating progression were taken together, there were 17 events in 193 treated patients and 42 events in 196 placebo control patients. Statistically significant reductions in these events were seen in ARC patients, AIDS patients and all patients.(ABSTRACT TRUNCATED AT 250 WORDS)