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Biomedical subjects

L M Chelstrom

Publications and source records attributed to L M Chelstrom.

32 records · Page 2Linked to original sources
PubMed1993

Human t(1;19)(q23;p13) pre-B acute lymphoblastic leukemia in mice with severe combined immunodeficiency.

Severe combined immunodeficient (SCID) mice were injected intravenously with 5 x 10(6) primary bone marrow (BM) blasts from newly diagnosed patients with E2A-PBX1 fusion transcript positive t(1;19)(q23;p13) pre-B acute lymphoblastic leukemia (ALL). A marked variation existed in the pattern and extent of leukemic cell engraftment in SCID mice challenged with t(1;19) pre-B ALL blasts. Blasts from some patients caused disseminated leukemia that was detected by histopathology and/or flow cytometry, whereas blasts from other patients produced occult leukemia that was only detected by flow cytometry and/or polymerase-chain reaction. Notably, the ability of primary t(1;19) pre-B ALL blasts to cause disseminated leukemia in SCID mice was associated with poor prognosis. Six of six patients whose blasts caused disseminated leukemia in SCID mice relapsed at a median of 7.8 months (range: 5.7 to 25.2 months). In contrast, the remaining four patients whose blasts did not engraft or only partially engrafted remain in complete remission at 28 to 47 months. A new E2A-PBX-1 fusion transcript positive t(1;19) pre-B ALL cell line (designated LC1;19) with the composite immunophenotype CD7-CD10+CD19+CD45-HLA-DR+C mu+ was established by expanding BM blasts from a SCID mouse, which died of human t(1;19) ALL at 7 weeks after inoculation of primary leukemic blasts from a t(1;19) ALL patient. This cell line caused disseminated and invariably fatal leukemia when greater than 10(4) cells were injected intravenously into SCID mice. Total body irradiation followed by syngeneic BM transplantation (BMT) showed limited efficacy against LC1;19 leukemia in SCID mice. To our knowledge, this study is the first to (1) examine the in vivo growth of primary t(1;19) pre-B ALL blasts in SCID mice and (2) show that leukemic blasts from a majority of newly diagnosed t(1;19) pre-B ALL patients cause disseminated human leukemia in SCID mice. Our results indicate that t(1;19) pre-B ALL is biologically heterogeneous with regard to its in vivo growth pattern in SCID mice, a feature that may be predictive of prognosis. The described LC1;19 SCID mouse model may prove particularly useful for designing more effective treatment strategies against poor-prognosis t(1;19) ALL.

Animals↗
PubMed1993

Effects of the intermolecular toxin-monoclonal antibody linkage on the in vivo stability, immunogenicity and anti-leukemic activity of B43 (anti-CD19) pokeweed antiviral protein immunotoxin.

We have successfully constructed highly potent and selective anti-CD19 PAP immunotoxins using each of the three crosslinking agents, SPDP, LC-SPDP, or SMPT, to generate an intermolecular bridge between the B43 MoAb and PAP toxin moieties. These immunotoxins were selectively immunoreactive with and cytotoxic against CD19+ B-lineage ALL cells. In this report, we compared (a) in vivo chemical, immunological, and biological stability, (b) in vivo immunogenicity, and (c) in vivo anti-leukemic activity of various B43-PAP immunotoxin constructs. Our data recommend the use of SPDP and SMPT rather than LC-SPDP for generation of B43(anti-CD19)-PAP immunotoxins as clinical anti-leukemic agents. To our knowledge, this is the first comparative analysis of the in vivo pharmacokinetic features, immunogenicity, and anti-leukemic activity of anti-CD19 PAP immunotoxins that were prepared with different heterobifunctional crosslinking agents.

Animals↗
PubMed1993

Effective immunochemotherapy of human t(4;11) leukemia in mice with severe combined immunodeficiency (SCID) using B43 (anti-CD19)-pokeweed antiviral protein immunotoxin plus cyclophosphamide.

Human mixed lineage leukemia cell line RS4;11 with the t(4;11)(q21;q23) translocation causes disseminated and invariably fatal leukemia in mice with severe combined immunodeficiency. Whereas an immunotoxin constructed from the murine anti-CD19(B43) monoclonal antibody and the plant toxin pokeweed antiviral protein (B43-PAP) has a potent in vitro anti-leukemic effect against clonogenic RS4;11 cells, its activity is further potentiated by the active cyclophosphamide congener mafosfamid. These intriguing observations prompted us to evaluate the in vivo antileukemic efficacy of combined immunochemotherapy employing B43-PAP immunotoxin plus cyclophosphamide against human t(4;11) leukemia cells in an RS4;11 severe combined immunodeficiency (SCID) mouse model system. Intravenous injections of B43-PAP or cyclophosphamide improved survival of SCID mice challenged with RS4;11 leukemia, as reflected by markedly prolonged median survival times. After intravenous inoculation of 5 x 10(7) RS4;11 leukemia cells, the median survival times were 41 days for saline-treated control mice (n = 12), 44 days for control mice treated with unconjugated B43 monoclonal antibody and PAP (n = 12), 56 days for mice treated with the control immunotoxin G17.2 (anti-CD4)-PAP (n = 6), 79 days for B43-PAP-treated test mice (n = 12), and 80 days for cyclophosphamide-treated test mice (n = 16). Notably, combined immunochemotherapy using B43-PAP plus cyclophosphamide was significantly more effective than either B43-PAP or cyclophosphamide alone. The median survival time for a total of 22 SCID mice undergoing combined immunochemotherapy with B43-PAP followed by cyclophosphamide (n = 12) or cyclophosphamide followed B43-PAP (n = 10) was > 150 days. The Kaplan-Meier estimates and standard errors of the probability of event-free survival at 5 months after inoculation of 5 x 10(7) RS4;11 cells were 21 +/- 13% for B43-PAP-treated mice, 7 +/- 6% for cyclophosphamide-treated mice, 90 +/- 10% for mice treated with B43-PAP followed by cyclophosphamide (n = 12), and 90 +/- 10% for mice treated with cyclophosphamide followed by B43-PAP (n = 10). Our results lead us to recommend that initial consideration be given to combined immunochemotherapy protocols using B43-PAP immunotoxin plus cyclophosphamide for treatment of refractory or relapsed t(4;11) leukemias.

Acute Disease↗
PubMed1993

In vivo anti-leukemic efficacy of anti-CD7-pokeweed antiviral protein immunotoxin against human T-lineage acute lymphoblastic leukemia/lymphoma in mice with severe combined immunodeficiency.

Mice with severe combined immunodeficiency (SCID) were injected with 1 x 10(7) MOLT-3 human T-lineage acute lymphoblastic leukemia cells to provide a model for the evaluation of anti-CD7-pokeweed antiviral protein (PAP) immunotoxin directed against the human CD7 antigen. Of control SCID mice (treated with phosphate-buffered saline, PBS) challenged intravenously with 1 x 10(7) MOLT-3 cells, 5/5 died at 29 to 35 days after inoculation, with a median event-free survival of 33 days. Similarly, 6/6 anti-CD19-PAP treated control SCID mice died of MOLT-3 leukemia at a median of 36 days. In contrast, treatment with anti-CD7-PAP (15 micrograms total dose in 5 micrograms intraperitoneal injections on days 1-3) significantly improved event-free survival of SCID mice challenged with 1 x 10(7) MOLT-3 cells. Of nine SCID mice treated with anti-CD7-PAP, four died at 54-149 days and five remained alive for > 172 days without clinical evidence of leukemia (median event-free survival > 172 days). When long-term survivors among the anti-CD7-PAP treated SCID mice were electively killed at 173 days to assess their leukemia burden, histopathologic examination and polymerase chain reaction provided evidence of disseminated leukemia in some of these mice. Intriguingly, marked differences in morphology, tissue distribution, and histologic pattern of organ invasion existed between leukemic blasts killing 100% of PBS-treated control mice at a median of 33 days and 'therapy-refractory' leukemic blasts detected in anti-CD7-PAP-treated long-term survivors. This novel SCID mouse model of disseminated human T-lineage ALL provides a unique in vivo system to investigate the therapeutic potential of new treatment strategies and to study possible mechanisms of in vivo immunotoxin resistance.

Animals↗
PubMed1992

Effective immunochemotherapy of CALLA+C mu+ human pre-B acute lymphoblastic leukemia in mice with severe combined immunodeficiency using B43 (anti-CD19) pokeweed antiviral protein immunotoxin plus cyclophosphamide.

A highly aggressive human CALLA+C mu+ pre-B acute lymphoblastic leukemia (ALL) cell line (NALM-6-UM1) causes disseminated and invariably fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). We used this SCID mouse model of human pre-B ALL to evaluate and compare, in a total of 434 SCID mice, the antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin and cyclophosphamide (CPA) as individual reagents and as combined immunochemotherapeutic regimens. B43-PAP plus CPA was superior to either the immunotoxin or drug alone, and combined immunochemotherapy markedly improved the event-free survival (EFS) of SCID mice challenged with NALM-6-UM1 pre-B ALL cells. Notably, 90% to 100% of SCID mice challenged with 1 x 10(6) leukemia cells and then treated with B43-PAP plus CPA combined immunochemotherapy regimens became long-term survivors, a result not achieved with B43-PAP alone or CPA alone. The advantage was particularly evident in mice inoculated with 5 x 10(6) leukemia cells. While neither 15 micrograms B43-PAP (median survival, 58 days) nor 1 mg CPA (median survival, 49 days) resulted in long-term EFS of SCID mice challenged with 5 x 10(6) NALM-6-UM1 pre-B ALL cells, the probability of EFS at 6 months was 50% +/- 16% for SCID mice treated with 15 micrograms B43-PAP plus 1 mg CPA (median survival, greater than 180 days) (P less than .0001). The probability of long-term EFS was only 14% +/- 7% for mice treated with 30 micrograms B43-PAP and 0% +/- 0% for mice treated with 1 mg CPA, but 40% +/- 16% for mice treated with 30 micrograms B43-PAP plus 1 mg CPA (P less than .0001). Similarly, the probability of EFS at 6 months was 40% +/- 16% for mice treated with 2 mg CPA alone, 70% +/- 15% for mice treated with 2 mg CPA plus 15 micrograms B43-PAP, and 70% +/- 15% for mice treated with 2 mg CPA plus 30 micrograms B43-PAP. Ten SCID mice in the B43-PAP plus CPA combined immunochemotherapy arms surviving long term after the inoculation of 5 x 10(6) NALM-6-UM1 pre-B ALL cells were electively killed at 174 to 181 days to assess their leukemia burden. We found no evidence of leukemia in any of the bone marrow specimens by two-color immunofluorescence and multiparameter flow cytometry.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

In vivo efficacy of B43 (anti-CD19)-pokeweed antiviral protein immunotoxin against BCL-1 murine B-cell leukemia.

We show that a highly aggressive subclone of murine BCL-1 B-lineage leukemia expresses a single 2.4-kb transcript hybridizing to the human CD19 cDNA probe and reacts strongly with the anti-human CD19 monoclonal antibodies (MoAb) B43, B4, Leu-12, and J3-119. In contrast to their strong reactivity with anti-human CD19 MoAb, BCL-1 cells show no reactivity with MoAb directed against human CD22, CD72, HLA-DR, IgD, or IgM. Western blot analysis of BCL-1 whole cell lysates with the anti-human CD19 MoAb J3-119 showed a single 69-Kd protein band, which was not detected by the negative control MoAb G19.4 (anti-CD3). In contrast to BCL-1 cells, normal BALB/c splenocytes or mouse splenocyte/myeloma hybridoma cell lines did not (1) express any transcripts that hybridized to the human CD19 cDNA probe, (2) react with B43/anti-CD19 MoAb, or (3) express the 69-Kd protein that reacts with the anti-human CD19 MoAb J3-119. Murine BCL-1 B-cell leukemia thus provides a unique model of disseminated B-lineage leukemia to evaluate the antileukemic efficacy of anti-CD19 immunotoxins. This model was subsequently used to evaluate the in vivo homing ability, pharmacokinetics, and antileukemic efficacy of B43 MoAb conjugated to the plant hemitoxin pokeweed antiviral protein (PAP). B43-PAP immunotoxin (1) showed strong and antigen-specific reactivity with BCL-1 cells, (2) promptly penetrated the spleens of leukemic mice, (3) rapidly reduced the BCL-1 leukemia burden of leukemic mice and, most importantly, (4) improved survival. Finally, B43-PAP immunotoxin was more effective against BCL-1 leukemia than 700 cGy (LD100/30) total body irradiation (TBI) followed by syngeneic bone marrow transplantation (BMT).

Animals↗
PubMed1992

In vivo efficacy of B43 (anti-CD19)-pokeweed antiviral protein immunotoxin against human pre-B cell acute lymphoblastic leukemia in mice with severe combined immunodeficiency.

A highly aggressive subclone of the human CALLA+C mu+ pre-B acute lymphoblastic leukemia (ALL) cell line NALM-6 (designated NALM-6-UM1) caused disseminated and fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). An intravenous challenge with 1 x 10(6) (NALM-6-UM1 cells caused 15 of 27 (56%) SCID mice to become paraplegic at 31 +/- 2 days (median = 33 days) and 27 of 27 (100%) mice to die of disseminated leukemia at 38 +/- 1 days (median = 39 days). We used this SCID mouse model of aggressive human pre-B ALL to evaluate the in vivo antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin. A 3-day treatment with nontoxic doses of B43-PAP markedly reduced the incidence of paraplegia and improved event-free survival (EFS) in SCID mice challenged with 1 x 10(6) NALM-6-UM1 pre-B ALL cells, as reflected by significantly higher cumulative proportions of mice free of paraplegia or alive at 1 to 7 months, as compared with phosphate-buffered saline (PBS) treated control mice. The Kaplan-Meier estimates and standard errors of the probability of developing paraplegia after inoculation of 1 x 10(6) NALM-6-UM1 cells was 64% +/- 10% for PBS-treated mice (median time to paraplegia = 37 days) (N = 27), 18% +/- 8% for mice treated with 15 micrograms B43-PAP (5 micrograms/mouse/d x 3 days) (N = 23) and 5% +/- 5% for mice treated with 30 micrograms B43-PAP (10 micrograms/mouse/d x 3 days) (N = 21). While 27 of 27 PBS-treated control SCID mice died of leukemia at 38 +/- 1 days (range = 24 to 54 days), only 16 of 44 B43-PAP-treated mice developed leukemia at 74 +/- 12 days (range = 30 to 182 days), consistent with greater than or equal to 6 logs kill of clonogenic NALM-6-UM1 cells in 64% of SCID mice. The Kaplan-Meier estimates and standard errors of the probability of long-term EFS after inoculation of 1 x 10(6) NALM-6-UM1 cells were 65% +/- 10% for mice treated with 15 micrograms B43-PAP and 60% +/- 11% for mice treated with 30 micrograms B43-PAP with a median survival time of greater than 7 months for both groups. In contrast, neither unconjugated B43 monoclonal antibody nor the anti-T-cell immunotoxin G17.2 (anti-CD4)-PAP decreased the incidence of paraplegia or improved EFS.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Treatment of BCL-1 murine B-cell leukemia with recombinant cytokines. Comparative analysis of the anti-leukemic potential of interleukin 1 beta (IL-1 beta), interleukin 2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF alpha), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), and their combination.

Murine BCL-1 B-cell leukemia provides a model of disseminated human B-lineage acute lymphoblastic leukemia (ALL) and non-Hodgkins lymphoma (NHL). This model was used to evaluate and compare the anti-leukemic efficacy of recombinant cytokines rIL-1 beta, rIL-2, rIL-6, rTNF alpha, rG-CSF, rGM-CSF and their combinations. Of these 6 cytokines tested, rG-CSF, rIL-1 beta, rIL-2, and rTNF alpha exerted a marked anti-leukemia/lymphoma activity, as reflected by significantly improved survival of treated mice after inoculation of BCL-1 cells. Notably, no additive or synergistic effects were observed when 2-4 cytokines were used in combination. To our knowledge, this report represents the first comparative analysis of recombinant cytokine treatment regimens in an animal model of disseminated B-lineage ALL/NHL.

Animals↗
PubMed1990

Changes in human skin blood flow by hyperthermia.

The heat-induced changes in blood circulation in human forearm skin were studied. With the use of laser Doppler flowmetry, it was possible to noninvasively monitor the velocity and volume of red cells, and thus the flow rate of red cells or blood flow in the human skin. When the skin surface was heated at 35 degrees -43 degrees C for 60 min, the laser Doppler flow (LDF) changed dynamically, indicating that the blood flow in human forearm skin could increase as much as 15-20 times during heating at 43 degrees C. Such an increase in laser Doppler flow resulted from dilation of arterioles and recruitment of capillaries, and also to a lesser extent, from an increase in the velocity of red cell flux. The increase in the velocity of red cell flux implies that arteriovenous anastomoses exist in the human forearm skin, in contradiction to the common view that human forearm skin is devoid of arteriovenous anastomosis.

Female↗
PubMed1990

Effects of a second heating on blood flow in tumors.

The blood flow in RIF-1 tumors of C3H mice, as measured with the 86Rb uptake method, declined markedly after a single heating at 43.5 degrees C or 44.5 degrees C for 1 h. However, preheating at 42.5 degrees C for 1 h significantly lessened the decrease in tumor blood flow caused by subsequent heating at 43.5 degrees C or 44.5 degrees C for 1 h. Such an influence of preheating on the effect of reheating in decreasing the tumor blood flow was significant as early as 6 h after the preheating, peaked at 36 h, and then decayed the following 2-3 days. In fact, a reheating at 43.5 degrees C for 1 h applied 36 h after a preheating at 42.5 degrees C for 1 h resulted in an increase rather than a decrease in blood flow. The cause of such a profound impact of preheating on the effect of reheating on the blood flow is unclear. However, circumstantial evidence including the histopathological appearance of tumors suggests that thermotolerance is induced in the blood vessels of the tumor as a result of preheating.

Animals↗
PubMed1989

The kinetics of vascular thermotolerance in SCK tumors of A/J mice.

Development of thermotolerance has been observed in diverse biological systems. Despite the important role of blood circulation in heat-induced tissue damage, little is known about vascular thermotolerance. The kinetics of vascular thermotolerance in SCK tumors of A/J mice was investigated in this study. A single heating at 43.5 degrees C or 44.5 degrees C for 1 hr caused marked damage in tumor vasculature, as demonstrated by a marked decrease in Rb-86 uptake (% of injected dose/g of dried tissue). The tumor vasculature became resistant or tolerant to subsequent heatings at those temperatures when the tumors were preheated at 42.5 degrees C for 1 hr. Vascular thermotolerance became significant at 5 hr and reached its maximum at 18 hr after preheating at 42.5 degrees C. When the vascular thermotolerance was at its peak, heating at temperatures as high as 44.5 degrees C for 1 hr could not reduce the tumor blood flow. The vascular thermotolerance decayed considerably but not completely at 72 hr after the preheating. The vascular thermotolerance may exert a profound implication on the response of tissues, including tumors, to multiple heatings.

Adaptation, Physiological↗
PubMed1989

Effects of temperature on blood circulation measured with the laser Doppler method.

The effects of local heating or cooling on skin microcirculation in volar aspect of human forearms was studied using laser Doppler flowmetry. When the skin was heated to 40 degrees C from a normal temperature of 32 degrees C, red cell flow (laser Doppler flow, blood flow) momentarily increased several fold and then temporarily decreased. The flow subsequently resumed a gradual increase reaching 10-15 times that of control in 30-40 min. When the skin temperature was returned to 32 degrees C after 60 min of heating, the blood flow momentarily declined but soon increased for several minutes before it began its major descent. When cooled from 32 degrees C to 5 degrees C, the flow momentarily decreased, but soon increased, surpassing the pre-cooling level. The flow began to decline when the cooling was prolonged for more than 15-20 min. The changes in flow corresponded well with the changes in number (volume) and speed of red cells. Laser Doppler flowmetry was found to be very useful for continuously monitoring microcirculatory blood flow in human skin.

Adult↗
PubMedDate not supplied

Effect of multiple heatings on the blood flow in RIF-1 tumours, skin and muscle of C3H mice.

The effect of one to five multiple heatings on blood flow in the RIF-1 tumour, skin and muscle of C3H mice was studied. When heated for 1 h at 43.5 degrees C the tumour blood flow increased 1.8 times, and rapidly decreased after the heating to less than half the control value. The 2nd-5th heatings at 43.5 degrees C, applied at 1- or 3-day intervals, caused no further significant change in the tumour blood flow. In the skin and muscle the blood flow increased 5 times when heated for 1 h at 43.5 degrees C, and remained at 1.5-2.0 times of control for 1-3 days after the heating. The blood flow in the skin and muscle, particularly in the skin, was further increased by the 2nd-5th heatings applied at 3-day intervals, but not at 1-day intervals, albeit the additional increase was very small. Consequently, whereas the tumour blood flow was 5-6 times greater than that in the skin and muscle before heating, it was only about 1.5-2.0 times greater than that in the skin and muscle during the 1st heating. The tumour blood flow became more or less similar to the normal tissue blood flow during the 2nd-5th heatings given at 3-day intervals. The decline in the vascular response in normal and tumour tissues to the 2nd-5th heatings suggested development of vascular thermotolerance.

Animals↗