Biomedical subjects

D M Goldenberg

Publications and source records attributed to D M Goldenberg.

At least 19 recordsLinked to original sources

PubMed2006

Advances in cancer therapy with radiolabeled monoclonal antibodies.

UNLABELLED: Two radiolabeled antibody products for the treatment of non-Hodgkin's lymphoma have been approved, thus indicating that cancer radioimmunotherapy (RAIT) has finally come of age as a new therapeutic modality, exemplifying the collaboration of multiple disciplines, including immunology, radiochemistry, radiation medicine, medical oncology, and nuclear medicine. Clinical trials are showing usefulness in other hematological neoplasms, but the treatment of solid tumors remains the major challenge, since the doses shown to be effective in hematological tumors are insufficient in the more common epithelial cancers. Nevertheless, use of RAIT in locoregional applications and in the treatment of minimal residual disease have shown promising RESULTS: There is also optimism that pretargeting procedures, including new molecular constructs and targets, will improve the delivery of radioactivity to tumors with less hematologic toxicity, and thus may become the next generation of RAIT.

Antibodies, Monoclonal↗

PubMed2005

Improved therapy of non-Hodgkin's lymphoma xenografts using radionuclides pretargeted with a new anti-CD20 bispecific antibody.

A comparison of the therapeutic efficacy of a new bispecific monoclonal antibody (bsMAb)-pretargeting system vs the conventional direct targeting modality was undertaken. A bsMAb was made by coupling the Fab' of a humanized anti-CD20 antibody to the Fab' of a murine antibody directed against the peptide histamine-succinyl-glycine (HSG). The tumor targeting of the bsMAb was separated from the subsequent delivery of the radionuclide-bearing HSG peptide conjugated with (111)In or (90)Y. Nude mice bearing s.c. Ramos human B-cell lymphomas were injected with the bsMAb and then, 48 h later, (111)In/(90)Y-HSG peptide was given. At 3 h postinjection, tumor/blood ratios for pretargeted (111)In-HSG-peptide were similar to that observed with the directly conjugated (111)In-anti-CD20 IgG at its highest level on day 7, but by day 1, tumor/blood ratios were about 10-fold higher than the IgG. Tumors progressed rapidly in animals given 800 microCi of (90)Y-HSG peptide alone, whereas 5/10 animals in the group pretargeted by the anti-CD20 bsMAb were tumor-free 18 weeks later. The antitumor response in animals administered the pretargeted (90)Y-HSG peptide was also significantly superior to treatment with the directly radiolabeled (90)Y-anti-CD20 IgG, whether given as a single injection (P<0.007) or as a divided dose (P=0.016). This bsMAb-pretargeting procedure significantly improves the therapeutic response of targeted radionuclides in non-Hodgkin's lymphoma, warranting further development of this method of radioimmunotherapy.

Animals↗

PubMed2004

High frequency of bone/bone marrow involvement in advanced medullary thyroid cancer.

High hematological toxicity has been observed with anti-carcinoembryonic antigen radioimmunotherapy (RIT) in medullary thyroid carcinoma (MTC), suggesting metastatic bone involvement (BI). This retrospective study evaluated the rate of BI in MTC patients enrolled in two phase-I/II RIT trials using anti-carcinoembryonic antigen x anti-diethylenetriamine pentaacetic acid bispecific antibodies and [(131)I]di-diethylenetriamine pentaacetic acid hapten. Thirty-five patients underwent bone scintigraphy, bone magnetic resonance imaging (MRI), and post-RIT immunoscintigraphy (IS). IS performed in MTC patients was compared with IS conducted in 12 metastatic colorectal carcinoma (CRC) patients. Quantitative analysis of bone uptake was performed in three MTC and three CRC patients. In the MTC group, bone scintigraphy detected BI in 56.6% of patients, MRI in 75.8%, and IS in 88.6%. BI was confirmed by undirected (random) bone marrow biopsy, by bone surgery, or by two positive imaging methods in 74.3% of the patients. Sensitivity per patient of bone scintigraphy, MRI, and IS were 72.7, 100, and 100%, respectively. In contrast, IS visualized BI in only 33.3% of CRC patients; bone uptake was lower in CRC than in MTC patients. Bone MRI combined with post-RIT IS disclosed a much higher BI rate in advanced MTC than previously reported in the literature.

Adult↗

PubMed2003

Interferon-gamma upregulates MUC1 expression in haematopoietic and epithelial cancer cell lines, an effect associated with MUC1 mRNA induction.

Epithelial mucin-1 (MUC1) is an important target antigen that it is overexpressed in both epithelial and haematological cancers including multiple myeloma (MM) and some lymphomas and leukaemias. MUC1 has adhesive and immunosuppressive properties, which may promote cancer progression. These studies evaluated the effect of IFNs on MUC1 expression, since these agents are widely used in clinical cancer therapy. MUC1 and interferon (IFN) receptor expression were measured by radioligand binding. Changes in MUC1 mRNA levels in response to IFN-gamma were assessed by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). IFN-gamma was found to be a more potent inducer of MUC1 expression than IFN-alpha. 125I-IFN binding studies indicated that both IFN receptors were expressed in most of the cell lines. With IFN-gamma treatment, there was upregulation of MUC1 mRNA. IFN-gamma has a more consistent and more potent effect upon MUC1 induction than IFN-alpha. The ability to upregulate MUC1 across a broad range of cancer types by a clinically available cytokine, IFN-gamma, has important implications for enhancing immunotherapeutic approaches targeting MUC1.

Antineoplastic Agents↗

PubMed2001

Unique molecular markers in human endometriosis: implications for diagnosis and therapy.

Endometriosis originates in the uterine lining and affects ~20% of reproductive-age women. The disease often causes chronic pelvic pain, affects ovulatory function and influences fertility. Although laparoscopic diagnosis of uterine endometriosis is quite specific, direct visualisation can be difficult or inaccurate in some circumstances, and it is not useful for diagnosing extra-abdominal disease. Laparoscopy is an invasive procedure, has significant morbidity and cannot be carried out frequently to monitor efficacy of therapy and the possibility of recurrence. Thus, a specific, non-invasive diagnostic test is required. One intriguing area of research uses the technology of radioimmunotargeting, which has previously been used for cancer detection. This technique could have potential for the specific detection and eventual treatment of endometriosis. A marker, eosinophil peroxidase (EPO), has been identified that is expressed in ~90% of endometriosis specimens, and is not expressed or only weakly expressed in normal endometrium. The US Food and Drug Administration has approved a monoclonal antibody to EPO for investigation as an immunoimaging agent in cancers that exhibit eosinophilia. EPO targeting using this antibody could be useful for detecting and/or treating endometriosis.

Journal Article↗

PubMed2001

Potent and specific antitumor effects of an anti-CD22-targeted cytotoxic ribonuclease: potential for the treatment of non-Hodgkin lymphoma.

LL2, an anti-CD22 monoclonal antibody against B-cell lymphoma, was covalently linked to the amphibian ribonuclease, onconase, a member of the pancreatic RNase A superfamily. LL2 increased in vitro potency (10 000-fold) and specificity against human Daudi Burkitt lymphoma cells while decreasing systemic toxicity of onconase. Monensin further increased potency of LL2-onconase on Daudi cells (IC(50), 20 and 1.5 pM, absence and presence of monensin, respectively). A 1-hour exposure to LL2-onconase was sufficient to kill Daudi cells in culture. These favorable in vitro properties translated to significant antitumor activity against disseminated Daudi lymphoma in mice with severe combined immunodeficiency disease. In mice inoculated with tumor cells intraperitoneally (ip), LL2-onconase (100 microg 5 times ip every day) increased the life span of animals with minimal disease 200%. The life span of mice with advanced disseminated Daudi lymphoma (tumor cells inoculated intravenously) was increased 135%. Mice injected with LL2-onconase tolerated a dose as high as 300 mg/kg. Because both onconase and LL2 are in clinical trials as cancer therapeutics, the covalently linked agents should be considered for treatment of non-Hodgkin lymphoma.

Animals↗

PubMed2001

Optimizing the use of combined radioimmunotherapy and hypoxic cytotoxin therapy as a function of tumor hypoxia.

Combined radioimmunotherapy (RAIT) and hypoxic cytotoxin therapy (SR4233 or NLCQ-1) have been evaluated with both modalities administered on the same day with only moderate improvement compared with the effects of RAIT alone. In a series of studies using oxygen electrodes, immunohistochemistry and radiotracers, we have demonstrated that RAIT induces a prolonged state of hypoxia in most tumors, without affecting the pO(2) levels in normal tissues. Using serial microelectrode measurements through subcutaneous (s.c.) GW-39 human colonic xenografts, we established that the median pO(2) was unrelated to the initial size of the tumor, over a range of sizes from 1.0 to 4.0 cm. Fourteen days after mice were given a 240-microCi dose of (131)I-MN-14 anti-carcinoembryonic antigen immunoglobulin G, their median pO(2) declined from 26.1 +/- 9.6 mmHg to 9.8 +/- 3.9 mmHg (p < 0.001). Using the radiotracer (3)H-MISO that accumulates in hypoxic regions, uptake in GW-39, LoVo and LS174T s.c. human colonic tumors increased 3.0- to 4.2-fold from day 14 through day 28 post-RAIT, but uptake of (3)H-MISO in CALU-3 tumors remained unchanged after RAIT. Normal tissue (liver, kidney, lung) uptake of (3)H-MISO did not exhibit significant changes. The increase in tumor hypoxia was also demonstrated visually using anti-PIMO staining of tumor sections. We postulated that sequential delivery of the 2 therapeutic agents, with the hypoxic cytotoxin given 2 weeks after RAIT when tumor pO(2) levels were at their nadir, would improve the therapeutic response above either modality alone or above the 2 agents delivered on the same day. Tumor growth was compared in mice given either RAIT or cytotoxin alone, the combined treatment on the same day or with the cytotoxin delivered 14 days after RAIT. Tumor size on day 35 for RAIT-treated and SR4233-treated GW-39 were 3.56 +/- 0.40 and 7.98 +/- 2.50 cm(3). When RAIT + SR4233 were delivered on the same day, tumor size dropped to 2.78 +/- 0.80 cm(3). If RAIT was given on day 0 and SR4233 on day 14, size further declined further to 1.74 +/- 0.32 cm(3) (p < 0.05 compared with same day delivery). For LS174T, tumor size on day 28 for RAIT-treated and SR4233-treated tumors were 1.14 +/- 0.36 cm(3) and 3.65 +/- 0.78 cm(3), respectively. When RAIT + SR4233 were delivered on the same day, size was 0.51 +/- 0.174 cm(3). If RAIT was dosed on day 0 and SR4233 was given on day 14, tumor size was 0.13 +/- 0.07 cm(3) (p < 0.05). Similar results were obtained for LoVo, but not for CALU-3 tumors. Another hypoxic cytotoxin, NLCQ-1, was also more efficacious 2 weeks after RAIT, compared with same-day dosing. Thus, information on tumor hypoxia after radioantibody therapy could be important for ascertaining a window of opportunity when the surviving tumor regions are most responsive to hypoxic cytotoxins.

Animals↗

PubMed2001

Response to radioimmunotherapy correlates with tumor pO2 measured by EPR oximetry in human tumor xenografts.

The efficacy of radiation treatment depends upon local oxygen concentration. We postulated that the variability in responsiveness of tumor xenografts to a fixed dose of radioimmunotherapy might be related to the tumor pO2 at the time that radioimmunotherapy was administered. We evaluated the growth of xenografts of CALU-3 tumors, a non-small cell lung carcinoma, in response to an 8.9-MBq dose of 131I-RS-7-anti-EGP-1 and correlated tumor growth rate with initial tumor pO2 measured by EPR oximetry. The greatest growth delay in response to radioimmunotherapy had the highest initial pO2, and the fastest-growing tumors had the lowest initial pO2. We then determined the dynamic effect of radioimmunotherapy on tumor pO2 by serial measurements of pO2 for 35 days after radioimmunotherapy. This information could be important for ascertaining the likelihood that a tumor will respond to additional doses as part of a multiple dose scheme. Serial tumor pO2 measurements may help identify a window of opportunity when the surviving tumor regions will be responsive to a second round of radioimmunotherapy or a second therapeutic modality such as chemotherapy or an anti-vascular agent. After radioimmunotherapy, there was an increase in tumor pO2 followed by a decrease below initial levels in most mice. Thus defined times may exist when a tumor is more or less radiosensitive after radioimmunotherapy.

Animals↗

PubMed2001

Single-cell cytotoxicity with radiolabeled antibodies.

Previous studies demonstrated the effective, antigen-specific killing of Raji B-lymphoma cells in vitro by radiolabeled anti-CD74, attributable largely to the high level of uptake, of approximately 10(7) antibody (Ab) molecules/cell/ day. This Ab is rapidly delivered to lysosomes for catabolism, so the radionuclide delivered accumulates primarily in lysosomes. In this study, we have tested Abs that bind to the same target cells in similar amounts, but remain primarily on the cell surface, to compare the potency of radioactivity delivered to the cell surface versus the cytoplasm. The Abs tested were anti-major histocompatibility complex class II and anti-CD20. 111In-labeled conjugates made with these two Abs killed cells very effectively and specifically, with 100% kill of sample of 5 x 10(5) cells. Because these Abs remain primarily on the cell surface, it would be predicted that residualizing radiolabels, which are trapped in lysosomes after Ab catabolism, would not be required, and this was observed, i.e., these two Abs were effective when labeled with either 125I or 131I, using conventional iodination, as well as with the residualizing label 111In-labeled DTPA. These results are in contrast to results obtained with anti-CD74, which required a residualizing radiolabel for effectiveness. The uptake of these radionuclides, in cpm/cell, was monitored, and this allowed estimation of the radiation dose delivered; the cytotoxicity observed was consistent with the estimated radiation dose delivered. To establish the generality of the results, we also demonstrated that 111In-labeled anti-CD74 effectively killed three other B-lymphoma cell lines, in addition to Raji and the adherent melanoma cell line SK-MEL-37. By using more potent radionuclides or conjugates of higher specific activity, this approach might be effective with other, lower density antigens.

Antibodies, Monoclonal↗

PubMed2001

Radioimmunotherapy of a human lung cancer xenograft with monoclonal antibody RS7: evaluation of (177)Lu and comparison of its efficacy with that of (90)Y and residualizing (131)I.

UNLABELLED: Tumor targeting and therapeutic efficacy of (177)Lu-labeled monoclonal antibody (mAb) RS7 (antiepithelial glycoprotein-1) was evaluated in a human nonsmall cell lung carcinoma xenograft model. The potential of (177)Lu-labeled RS7 was compared with that of RS7 labeled with (90)Y and a residualizing form of (131)I. METHODS: A 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) conjugate of RS7 was used for radiolabeling with (177)Lu-acetate or (88/90)Y-acetate. Biodistribution and therapy studies were conducted in nude mice with subcutaneous Calu-3 xenografts. Therapy studies were performed using the maximal tolerated doses (MTDs) of (90)Y-DOTA-RS7 (3.9 MBq [105 microCi]) and (177)Lu-DOTA-RS7 (10.2 MBq [275 microCi]) and compared with the data obtained using the MTD (13.0 MBq [350 microCi]) of a residualizing form of (131)I-RS7. RESULTS: Radiolabeling of RS7-DOTA conjugate with (177)Lu-acetate was facile. (177)Lu-DOTA-RS7 displayed biodistribution results that were nearly identical to that of the (88)Y analog in a paired-label study. The mean percentage injected doses per gram (%ID/g) for (177)Lu-RS7 and (88)Y-RS7 (in parentheses) in tumor were 38.3 %ID/g (39.1 %ID/g), 63.0 %ID/g (66.0 %ID/g), 63.0 %ID/g (65.8 %ID/g), and 34.0 %ID/g (34.9 %ID/g) on days 1, 3, 7, and 14, respectively. Elimination of established tumors, with an initial mean tumor volume of 0.24 cm(3), was shown using doses of (177)Lu-DOTA-RS7 ranging from 5.6 to 9.3 MBq (150--250 microCi) per nude mouse, with no significant difference in response rate noted between the doses in this range. Specificity of the therapeutic effect was shown in an isotype-matched control experiment, in which (177)Lu-DOTA-RS7 was markedly more effective than the (177)Lu-DOTA control antibody. A comparison of the therapeutic efficacies of (177)Lu-DOTA-RS7 and (90)Y-DOTA-RS7, using mice with established tumors with an initial mean tumor volume of 0.85 cm(3), indicated similar tumor growth inhibition and similar tumor regrowth profiles. The therapy data were similar to those obtained with residualizing (131)I-RS7 obtained at the same time. CONCLUSION: (177)Lu-RS7 is an effective radioimmunoconjugate for radioimmunotherapy. With its radiophysical properties similar to those of (131)I, coupled with its facile and stable attachment to mAb, (177)Lu promises to be an alternative to (131)I, and a complement to (90)Y, in radioimmunotherapy.

Animals↗

PubMed2001

Therapy of disseminated B-cell lymphoma xenografts in severe combined immunodeficient mice with an anti-CD74 antibody conjugated with (111)indium, (67)gallium, or (90)yttrium.

A radiolabeled antibody (Ab) to CD74 (the MHC class II invariant chain, Ii) was shown previously to effectively kill human B-lymphoma cells in vitro. Conjugates with both Auger electron and beta-particle emitters were able to kill cells, but the former displayed less nonspecific toxicity in the in vitro assay used. In this report, we have extended the studies to an in vivo model of tumor growth. The human B-cell lymphoma Raji was injected i.v. into severe combined immunodeficient mice, and radiolabeled Abs were injected at various times after tumor inoculation. The maximum tolerated dose (MTD), as well as lower doses, was tested. Tumor growth was monitored by hind-leg paralysis. With a 3-5-day interval before Ab injection, anti-CD74 conjugated to either (111)In or (67)Ga, at a dose of 240-350 microCi/mouse, produced a strong therapeutic effect, with greatly delayed tumor growth, and many of the treated mice were tumor free for >6 months. Control mice became paralyzed in 16-24 days, uniformly. Treatment at later time points (9-day interval) had little therapeutic effect. The MTD was required for optimal therapy. With the beta-particle emitter (90)Y, the MTD was much less, 25 microCi/mouse, and at this dose there was only a weak therapeutic effect. In conclusion, the data suggest that low-energy electrons are more effective than beta-particles in this model system. These results may be applicable to humans, particularly in the case of micrometastatic disease. This approach may also be effective with other Abs that accrete in large amounts.

Animals↗

PubMed2001

Chronotherapy and chronotoxicity of the cyclooxygenase-2 inhibitor, celecoxib, in athymic mice bearing human breast cancer xenografts.

PURPOSE: Inhibition of the enzyme cyclooxygenase with celecoxib is cytotoxic in a variety of solid tumor cell lines. Previous work has shown that by charting circadian rhythms, it has been possible to find optimal times to deliver a dose of drug, such that it is most efficacious in killing cancer cells and least harmful to normal tissues. Therefore, we examined the time dependence of toxicity (chronotoxicity) and of antitumor effects (chronotherapy) of celecoxib to determine optimal time of day for dosing with respect to light-dark cycles. EXPERIMENTAL DESIGN: Celecoxib was administered i.p. for 10 days (5 days on, 2 days off, 5 days on) to nude mice bearing s.c. breast xenografts. Body weight, peripheral blood cells, clinical chemistry, and tumor growth were monitored. RESULTS: The highest tolerance (100% survival) was found at 7 HALO and the least occurred at 17 h after light onset (HALO; 10% survival). Chronotherapy at a 20-mg/kg dose varied between the seven HALO evaluated and between the three breast tumors (MCF-7, ZR-75-30, and MDA-MB-468) studied. When the maximum tolerated dose (MTD) of celecoxib was optimized for each HALO, we found that at 7-10 HALO, the MTD was 25 mg/kg, whereas at 17-20 HALO; the MTD was only 10 mg/kg. Tumor regression was observed when dosing was done at 23 HALO to 7 HALO (5 a.m. to 1 p.m.), whereas no therapeutic response was observed when dosing was done at 10-13 HALO (4 p.m. to 7 p.m.), and rapid tumor growth was noted when dosing was done at 17 HALO (11 p.m.). CONCLUSIONS: Tumor growth response to the MTD at each HALO revealed that there was no clear relationship between dose administered and therapeutic response. COX-2 expression was not able to explain either the chronotherapy or the chronotoxicity results obtained.

Animals↗

PubMed2000

Achievement of high cell density and high antibody productivity by a controlled-fed perfusion bioreactor process.

Controlled feeding of nutrient supplements to a cell culture to enhance monoclonal antibody productivity has been practiced widely in high-yield, fed-batch processes. In this study, a similar feeding concept has been applied to a perfused culture and evaluated for the effects on bioreactor productivity and product quality. Our experimental results show that, by using such a "controlled-fed perfusion" approach, the volumetric antibody productivity (antibody per liter per day) was significantly increased by nearly twofold over the perfusion process, and surpassed fed-batch and batch processes by almost tenfold. The substantial boost in the overall productivity is attributable primarily to the combined effects of increased cell density as well as reduced product dilution. Both were achieved through careful nutrient supplementation in conjunction with metabolite minimization. As the manufacturing process evolved from roller bottles to the controlled-fed perfusion bioreactor system, the immunoreactivity and the cDNA sequences of the antibody were well preserved. However, the product glycosylation distribution patterns did alter. The controlled-feed perfusion process demonstrated a unique encompassment of the advantages of fed-batch and perfusion methods; that is, high product concentration with high volume throughput. Therefore, it may be very suitable for large-scale production of monoclonal antibodies.

Animals↗

PubMed2000

Carcinoembryonic antigen immunoscintigraphy complements mammography in the diagnosis of breast carcinoma.

BACKGROUND: An adjunctive noninvasive test that is predictable and highly specific for breast carcinoma would complement the high false-positive rate of mammography in certain patients. METHODS: This prospective, multicenter study evaluated the accuracy, safety, and immunogenicity of carcinoembryonic antigen (CEA) antibody imaging in women with known or suspected breast carcinoma. Scintigraphic breast images were obtained approximately 3-8 hours after the administration of technetium 99m ((99)Tc) labeled anti-CEA Fab' and correlated with histopathology. RESULTS: The (99)Tc labeled anti-CEA Fab' detected tumor CEA expression in 46 of 49 women (94%) initially entered with known primary breast carcinoma regardless of histology or serum CEA levels. In women scheduled for biopsy confirmation of mammographic and physical examination findings, 104 (99)Tc labeled anti-CEA Fab' studies had a sensitivity of 61% (17 of 28 cases) and a specificity of 91% (69 of 76 cases). In total, (99)Tc labeled anti-CEA Fab' detected 52 of 62 invasive ductal carcinomas, 5 of 5 invasive lobular carcinomas, and 3 of 6 noninvasive tumors (2 ductal carcinomas in situ and 1 intracystic papillary carcinoma). Tumor size significantly affected sensitivity (P = 0.041), with 11 of 14 missed lesions </= T1, and proliferative histology significantly affected specificity (P = 0.012), with 5 of 7 false-positive tumors being premalignant. In 50 breast carcinoma patients, (99)Tc labeled anti-CEA Fab' also demonstrated axillary lymph node involvement regardless of serum CEA levels, with a sensitivity of 80% when more than three lymph nodes were positive. No immune response or other meaningful side effects occurred. CONCLUSIONS: (99)Tc labeled anti-CEA Fab' had high specificity and positive predictive values for breast carcinoma and the majority of false-positive studies were associated with an increased risk of malignancy. Improved imaging techniques, including dedicated gamma cameras for breast and axillary lymph node imaging, will likely improve the test's sensitivity for smaller lesions.

Adult↗

PubMed2000

Anti-oxidant vitamins reduce normal tissue toxicity induced by radio-immunotherapy.

Our purpose was to determine whether the administration of anti-oxidant vitamins could reduce dose-limiting toxicity from radio-immunotherapy (RAIT) and thereby allow higher escalation of RAIT doses. Lipophilic vitamins A and E were administered i.p. and hydrophilic vitamin C was administered i.m. for 14 days (3 days pre-RAIT through 11 days post-RAIT) alone or with bone marrow transplantation (BMT) to either BALB/c mice for toxicity studies or to nude mice bearing s.c. GW-39 human colonic cancer xenografts for therapy studies. The maximal tolerated dose (MTD) of RAIT ((131)I-MN14 anti-CEA IgG) that results in no lethality was determined for mice that did not receive vitamins or BMT and those that did receive one or both interventions. Body weight, peripheral white blood cell (pWBC) and platelet (PLT) counts and tumor growth were also measured. Administration of vitamins (equivalent of 3.5 IU/day vitamin A, 0.107 IU/day vitamin E and 4.0 mg/day ascorbic acid) to mice along with BMT increased the MTD by 42% and reduced body weight loss associated with RAIT. Vitamins also reduced the magnitude of RAIT-induced myelosuppression. As early as day 7 after RAIT, vitamins increased WBC counts following both a 400 microCi and a 500 microCi dose. On day 14 after the 400 microCi dose of RAIT (day 7 post-BMT), the additive effect of BMT and vitamin could be detected. Tumor growth was not adversely affected by vitamin administration.

Animals↗

PubMed2000

Sphingomyelin potentiates chemotherapy of human cancer xenografts.

We propose that one manifestation of altered sphingolipid metabolism within tumor cells may be a reduced sensitivity to anti-cancer therapies because of an inability to produce a sufficient apoptotic signal via sphingomyelin hydrolysis to ceramide. If so, then sphingomyelin administration could reverse this effect and increase a tumor's sensitivity to chemotherapy. In vivo, intravenous sphingomyelin (10 mg/day, 7 days) potentiated 5-fluorouracil chemotherapy (0.45 mg/day, 5 days) when co-administered to HT29 human colonic xenograft-bearing nude mice. In vitro, sphingomyelin (SM) at its maximum tolerated concentration increased 5-fluorouracil and doxorubicin sensitivity of HCT15 and MOSER (1 mg/ml SM) and LS174T and SW480 human colonic tumor cells (0.1 mg/ml) approximately 100-300%. At 1 mg/ml SM, however, no effect was seen using HT29, LoVo and WiDr cells. There was no sensitization of normal human umbilical cord endothelial cells. Thus, sphingomyelin co-administration may be one method to improve the selective efficacy of chemotherapy in some tumors, possibly through enhancement of the apoptotic response.

Animals↗

PubMed2000

Plasma FLT3-L levels predict bone marrow recovery from myelosuppressive therapy.

BACKGROUND: During the recovery period after anticancer myelosuppressive therapy, hematopoietic progenitor cells become mitotically active in order to replenish the bone marrow compartment and remain hyperproliferative even after normalization of peripheral white blood cells and platelets. At this stage, the progenitors are more radiosensitive and chemosensitive. Dosing patients with additional cytotoxic therapy during this phase will likely result in more severe toxicity. For example, the authors have noted that the red bone marrow (RM) dose resulting from radioantibody therapy does not correlate with observed bone marrow toxicity. Several patients given similar RM doses had Grade 3 or 4 toxicity, whereas others had Grade 0-2 toxicity even though their white blood cell (WBC) and (PLT) counts were normal at the time of dosing. The goal of these studies was to establish a noninvasive predictive marker of bone marrow activity that could determine stem cell and progenitor cell recovery from previous myelosuppressive therapy. METHODS: A retrospective study was conducted to quantitate plasma levels of 5 cytokines regulating hematopoiesis, namely, 2 stimulatory fms-like tyrosine kinase (FLT3-L) and stem cell factor (SCF) and 3 inhibitory growth factors tumor necrosis factor-alpha (TNFalpha), tumor growth factor-beta, and macrophage inflammatory protein (MIP-1alpha), by immunoassay in 43 patients enrolled in clinical trials at Garden State Cancer Center in Belleville, New Jersey. All patients had had previous chemotherapy with a duration of 1-24 months. The serum cytokine values were correlated with the magnitude of leukopenia or thrombocytopenia following a single dose of radioantibody as the cytotoxic therapy. RESULTS: Plasma FLT3-L levels predicted excess platelet toxicity in 13 of 16 patients (mean = 225 +/- 106 pg/mL) and resulted in a false-positive in only 3 of 27 other patients (mean = 80 +/- 41 pg/mL). Plasma FLT3-L > 135 pg/mL resulted in 81% sensitivity and 89% and 86% specificity and accuracy, respectively, for predicting excess toxicity caused by additional cytotoxic therapy. The positive likelihood ratio was 7.5 (95% confidence interval, 2.5-22.5) and the negative likelihood ratio was 0.19 (95% confidence interval, 0.05-0.67). CONCLUSIONS: Elevated plasma FLT3-L in patients who previously received chemotherapy is a predictive measure of the stage of recovery of the bone marrow compartment. FLT3-L seems to identify the likelihood that the patient will experience Grade > or = 3 thrombocytopenia if additional cytotoxic therapy is administered. Knowledge of bone marrow activity should permit therapy that is more aggressive by establishing the earliest possible time for dosing with any cytotoxic agent for which myelosuppression is the dose-limiting toxicity.

Antineoplastic Agents↗

PubMed2000

Localization of an antibody to CD74 (MHC class II invariant chain) to human B cell lymphoma xenografts in nude mice.

The tumor-specific localization of an anti-CD74 Ab, LL1, was demonstrated in nude mice bearing xenografts of human B-cell lymphoma. This Ab, conjugated to radionuclides emitting Auger electrons, including 125I and 111In, was previously reported to kill tumor cells in vitro effectively and specifically. The cytotoxic potency of this Ab is due to its uptake and catabolism at a very high level, which also affected the Ab biodistribution experiments. Thus, Ab localization to the tumor was only detected if a "residualizing" radiolabel was used, meaning a label that is trapped within cells, usually within lysosomes, after catabolism of the Ab to which it was conjugated. Similar results were obtained with three different residualizing labels: 111In conjugated via the chelators benzyl diethylenetriaminepentaacetic acid (DTPA) or 1.4,7,10-tetra-azacyclododecane-N, N', N", N"'-tetraacetic acid (DOTA), or 131I-dilactitol-tyramine, a residualizing form of iodine. The Ab protein dose could be high, 0.5 mg/mouse, without causing a decrease in specific tumor uptake, probably reflecting the high capacity for uptake. Moreover, tumors of moderate size were found to cause rapid, specific removal of the Ab from the blood, also a result of catabolic processes. This induced blood clearance naturally affected the Ab localization experiments, but this factor could be circumvented by increasing the Ab protein dose. Using a different Ab, anti-(mature MHC class II), the ability of Ab to penetrate relatively large solid tumors was investigated. Complete saturation of antigenic sites was observed in tumors up to 0.3 g in size, but quite high Ab protein doses were required, 5.0 mg/ mouse. These results provide a rationale for attempting therapy with radiolabeled LL1.

Animals↗