Reimplantation Of Tumor Cells Research Articles

Abstract 2640: An innovative site-specific dual-payload antibody drug conjugate (dpADC) combining a novel Topo1 inhibitor and an immune agonist delivers a strong immunogenic cell death (ICD) and antitumor response in vitro and in vivo

Abstract Background: Antibody-drug conjugate, also known as a targeted chemotherapy, leverages the targeting feature of mAb and the efficient cell-killing ability of cytotoxin to deliver cytotoxic drugs to tumor specifically. Among the FDA approved 15 ADCs and over 100 in clinical trial, the majority contains a single type cytotoxin payload. Combination of chemotherapies or multiple agents are widely therapeutic approach to enhance treatment efficiency, although frequently combo therapies could lead to higher toxicity, long term chemotherapies could result in drug resistance and tumor relapse. To solve above challenge, here we report an innovative dual-payload antibody-drug conjugate (dpADC) with 2 type of different drug payloads with different MoA, the conjugate is constructed based on unique enzymatic site-specific conjugation technology iLDC/iGDC. The dpADC leads to an enhanced immunogenic cell death (ICD) and antitumor response in vitro and in vivo via a synergistic MoA. Results: A novel Topo1 inhibitor TopoIx and an immune agonist were stably conjugated to an anti-Trop2 mAb in a site-specific manner, conjugate homogeneity and precise DAR were characterized. The dpADC showed a strong cytotoxicity on the proliferation of Trop2-expressing cells, meanwhile bystander killing activity of TopoIx also effectively inhibits growth ofTrop2-negative cells. This dpADC also triggers IP10/IL6 secretion when co-cultured with PBMC/monocyte and Trop2-positive cancer cells, with induction level correlated with Trop 2 expression level. No free payload was released after 96hr incubation at 37 oC in human plasma, demonstrating high linker stability. The dpADC demonstrated a robust antitumor response against diverse Trop2+ tumors in vivo. Its’ combination with anti-mPD-1 resulted in synergistic anti-tumor response. In a tumor rechallenge model, the mice that had cleared of Trop2+ tumors after dpADC treatment were protected against the re-implantation of tumor cells with same or different neoantigen, suggesting the presence of a robust immunological memory. Conclusion: In summary, this novel dpADC demonstrates potent antitumor activities in vitro and in vivo and leads to an enhanced tumor cell killing ability and a prolonged immunological memory via a synergistic MoA. Based on this site-specific, dual-enzyme orthogonal catalytic conjugation platform, we can easily integrate MoA-varied drugs in one targeting modality to realize a synergistic, durable anti-tumor therapy. Citation Format: Meijun Xiong, Beibei Fan, Xinju Gao, Yajun Sun, Cao Lv, Yu Si, Xiao Liu, Lili Shi, Paul H. Song, Gang Qin. An innovative site-specific dual-payload antibody drug conjugate (dpADC) combining a novel Topo1 inhibitor and an immune agonist delivers a strong immunogenic cell death (ICD) and antitumor response in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2640.

Possible tumour cell reimplantation during curative endoscopic therapy of superficial Barrett’s carcinoma

Background and aimsEndoscopic resection has been established as curative therapy for superficial cancer arising from Barrett’s oesophagus (BE); recurrences are very rare. Based on a case series with unusual and...

Lytic Effects of Water on Bladder Cancer Cell Lines – Implications for Clinical Use of Water Irrigation to Reduce Recurrence

Recurrence of bladder cancer (BC) following initial management with transurethral resection of bladder tumour (TURBT) is observed in 15-60% of patients. Intraoperative tumour spillage can be a concern during TURBT, given that it can lead to tumour cell re-implantation and local recurrence. Immediate post-TURBT instillation of chemotherapy is effective at reducing recurrence, but remains underutilised. There is evidence that mechanically washing out free-floating tumour cells with bladder irrigation may be a comparable but less expensive or toxic alternative. Irrigating with sterile water may be more effective compared to iso-osmotic irrigants (such as saline) by virtue of causing additional osmotic cytolysis, but this has not been well characterised. This in vitro study aimed to ascertain the time-course of osmotic effects of water on BC cell lines to guide its meaningful clinical usage. In-vitro studies were conducted on HT1197 and HT1376 BC cell lines, red blood cells, and white blood cells. Each cell line was exposed to either water, 0.9% saline or 1.5% glycine. Cell counts (in triplicate) were performed at 10, 20, and 40 minutes, and then hourly for up to 5 hours using a haemocytometer. Cell viability was determined using Trypan blue. In both BC cell lines, saline and glycine caused respectively ∼50% and 65% reduction in the number of viable cells after a minimum of 1 hour of exposure (p<0.0001 vs time 0). Conversely, the effect of water was rapid, inducing 100% cell lysis in under 20 minutes (p = 0.0001 vs time 0), while saline and glycine had no measurable effect in this timeframe (p = 0.9255 and 0.0662 vs time 0, respectively). For red blood cells and white blood cells, water also precipitated cell lysis within 10 minutes, whilst saline and glycine had minimal effect. These results suggest that water has a rapid osmolytic effect upon BC cells. If confirmed using ex vivo samples from patients, this suggests that a short period of irrigation with water may potentially be effective in reducing BC recurrence.

MP72-17 OSMOTIC CYTOLYTIC EFFECTS OF WATER ON CELL COUNTS – IMPLICATIONS FOR CLINICAL USE OF WATER IRRIGATION TO REDUCE NON-MUSCLE INVASIVE BLADDER CANCER RECURRENCE

You have accessJournal of UrologyBladder Cancer: Non-invasive III (MP72)1 Apr 2020MP72-17 OSMOTIC CYTOLYTIC EFFECTS OF WATER ON CELL COUNTS – IMPLICATIONS FOR CLINICAL USE OF WATER IRRIGATION TO REDUCE NON-MUSCLE INVASIVE BLADDER CANCER RECURRENCE Ruchira Nandurkar*, Mo Li, Pavel Sluka, Hady Wardan, Ian Davis, and Shomik Sengupta Ruchira Nandurkar*Ruchira Nandurkar* More articles by this author , Mo LiMo Li More articles by this author , Pavel SlukaPavel Sluka More articles by this author , Hady WardanHady Wardan More articles by this author , Ian DavisIan Davis More articles by this author , and Shomik SenguptaShomik Sengupta More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000952.017AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recurrence of Non-Muscle Invasive Bladder Cancer (NMIBC) following initial transurethral resection of the bladder tumour (TURBT) is observed in 40-80% of patients. One cause of this is intraoperative tumour exfoliation during resection, leading to tumour cell re-implantation and local recurrence. Immediate post-TURBT instillation of intravesical chemotherapy is effective at reducing recurrence, but remains underutilised. A potentially less expensive or toxic alternative may be to mechanically wash out free-floating tumour cells via irrigation. Irrigating with sterile water may be even more effective compared to iso-osmotic irrigants (such as saline) by virtue of osmotic cytolysis in addition to rinsing out exfoliated cells, although this has not been well characterised. The aim of this study was to ascertain the impact of water on cell viability on both in vitro and ex vivo samples. METHODS: Two bladder cancer cell lines (HT1197 and HT1376) were cultured, and exposed to water, 0.9% saline or 1.5% glycine for up to 5 hours. Viable and non-viable cells (determined using trypan blue staining) were manually counted on a haemocytometer. Similarly, hourly 200mL washout samples from 19 patients receiving 3 hours of either saline or water irrigation following TURBT were collected for cell counting. Trends for cell numbers over time were assessed using Friedman’s test, with statistical significance at p<0.05. Ethics approval was granted for this in vivo trial. RESULTS: In vitro, exposure to water led to a rapid decline in viable cells to zero within the first 20 minutes, whereas viable cell numbers slowly declined but remained detectable up to 5 hours when exposed to saline or glycine. 11 patients received water irrigation in vivo, and their median viable cell count reduced from 20 x 103 at time 0 to zero cells within one hour and beyond (p = 0.01). In contrast, saline-irrigated patients had a median viable cell count of 50 x 103 initially, which decreased to 8 x 103 after one hour and then remained stable, never decreasing to zero cells (p = 0.98). Immunohistochemistry on ex vivo samples showed significant numbers of bladder epithelial cells in saline irrigated patients in contrast to water irrigated patients. CONCLUSIONS: Our results demonstrate that water has an osmolytic effect upon bladder cancer cells in vitro and reduces the number of cells detected in catheter washout effluent in vivo. This suggests that a short period of irrigation with water post-TURBT may be a viable intervention in reducing NMIBC recurrence. Source of Funding: Trial sponsored by ANZUP Below-The-Belt Grant © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1081-e1081 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ruchira Nandurkar* More articles by this author Mo Li More articles by this author Pavel Sluka More articles by this author Hady Wardan More articles by this author Ian Davis More articles by this author Shomik Sengupta More articles by this author Expand All Advertisement PDF downloadLoading ...

A gel system for single instillation of non-muscle-invasive bladder Cancer: A “divide-and-rule” strategy

Single instillation (SI) reduces recurrence of non-muscle-invasive bladder cancer by chemoresecting floating tumor cells and residual tumor lesions (RTLs) after transurethral resection of the bladder, but with limited efficacy. Current studies improved this by prolonging retention time and increasing penetration to bladder wall, ignoring that the two separate factors should be treated in different ways. Here, we introduced a smart gel system-based SI to prevent re-implantation of tumor cells (RTCs) and ablate RTLs in a “divide-and-rule” approach. The gel system was synthesized by PEG-PAMAM and dextran aldehyde and composed of gold nanorods and gemcitabine for photothermal therapy and chemotherapy, respectively. It was developed to provide dextran aldehyde-selective adhesion with tissue amines. Since tumor surface expressed high levels of collagen, the exposed amines could act as adhesion points for the gel system. Thus, the gel presented more affinity to tumor tissues. When being instilled, it could form a protective layer on the inner face of the entire bladder wall immediately, preventing RTCs in early time. And it persisted long at the tumor site, ablating RTLs. Our data proved the gel system improved intravesical treatment efficacy in a “divide-and-rule” approach and might be a promising treatment strategy for SI.

Abstract 1387: Enhanced recruitment of tumor microenvironment components in A549 xenografts with acquired resistance to sorafenib

Abstract Acquired drug resistance represents a major obstacle to effective cancer treatment. Sorafenib is an oral multikinase inhibitor with proven efficacy for various types of advanced solid tumors, including non-small cell lung carcinomas (NSCLC). However, its clinical response is often short lived due to the emergence of acquired resistance. The objective of our ongoing project is to identify potential mechanisms underlying the acquisition of sorafenib resistance using in vivo models of A549 human NSCLC xenograft in athymic nude mice. The in vivo sorafenib-resistant tumor model was established by exposing A549 xenografts to once daily treatment with 40 mg/kg of sorafenib for 4 months. Cells isolated from fresh sorafenib-resistant A549 tumors were propagated in vitro and then reimplanted into the same strain of mice. Tumor tissues obtained from the primary and secondary A549 xenografts were subjected to Western blot and immunohistrochemistry analyses. The in vitro study demonstrated that there was no statistically significant difference in the sensitivity to sorafenib treatment between A549 parental cells and tumor cells derived from sorafenib-resistant A549 xenografts. In the in vivo study, relatively accelerated tumor growth rate was observed in 4 out of 10 sorafenib-treated animals bearing the primary A549 xenografts. Re-implantation of tumor cells derived from the sorafenib-resistant A549 xenografts into the secondary mice showed relatively rapid tumor growth in 6 out of 7 sorafenib-treated tumor bearing animals. Preliminary results from the immunofluorescence analysis of frozen tumor sections revealed that the expression of CD31 and α-smooth muscle actin (α-SMA) in sorafenib-resistant primary A549 tumors was significantly reduced compared with the untreated A549 tumors. In contrast, the expression of α-SMA in the secondary sorafenib-resistant A549 tumors was upregulated as compared with that in the primary A549 tumors, while the CD31 expression in the secondary tumors was similar to that in the primary control tumors. Moreover, in the primary A549 tumors, α-SMA immunofluorescence was often observed immediately adjacent to tumor microvessels; whereas in the secondary sorafenib-resistant tumors, α-SMA immunofluorescence mainly appeared in the stromal cells that were involved in the fibrous sheaths surrounding tumor cell nests. Overall, observations from the preliminary study suggest that the secondary sorafenib-resistant tumors have an increased ability to recruit stromal cells, which in turn promote resistance to sorafenib treatment. Further studies are currently underway to explore the potential mechanism associated with the enhanced recruitment of stromal cells in secondary sorafenib-resistant tumors. Citation Format: Qingyu Stephanie Zhou, Xiaofang Guo. Enhanced recruitment of tumor microenvironment components in A549 xenografts with acquired resistance to sorafenib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1387. doi:10.1158/1538-7445.AM2015-1387

Immunohistochemical expression of MMP9, as a marker of local invasion in Hodgkin’s and Non-Hodgkin’s lymphoma of the head and neck region

Background: Malignant lymphoma is the generic term given to tumors of the lymphoid system and specifically of lymphocytes and their precursor cells, While all lymphomas are malignant neoplasms, there is a wide spectrum of clinical behavior, with some following an indolent clinical course and others behaving in an aggressive manner (will causing death in a short time frame if left untreated). The metastatic process involves intravasation and extravasation of tumor cells, followed by reimplantation of tumor cells, formation of a new tumor stoma, Degradation of the extracellular matrix and components of the basement membrane by proteases facilitates the detachment of tumor cells, their crossing of tissue boundaries, and invasion into adjacent tissue compartments. The importance of tumor-associated proteases in invasion and metastasis has been demonstrated for a variety of solid malignant tumors. MMP family has been implicated in tumor cell invasion and metastasis. Material and methods: This study included 67 formalin-fixed, paraffin-embedded histopathologically diagnosed lymphoma blocks (head and neck lesions), 24 Hodgkin’s Lymphoma and 43 Non Hodgkin’s Lymphoma. Immunohistochemical (IHC) evaluation of MMP-9 monoclonal antibodies), in relation to the clinicopathological parameters was assessed. Results: The mean of expression of MMP-9 in NHL was higher (65.4±18) than that in HL (56.7±21.4) though it did not reach the level of statistical difference P > (0.05), while the mean of expression of MMP-9 in relation to tumor grades was different as it had a value of (72±14.1) in low grade tumors, (68.3±15) in the intermediate grade tumor and (61.4±20.7) in high grade tumors; consequently, this difference did not reached the level of statistical significance P(ANOVA) >0.05 . MMP 9 had no statistical significant correlation in regard to its mean in HL subtypes. Conclusions: This study had shown that there was no significant correlation between age and mean of expression of MMP-9 in HL and NHL. There was no statistical significant difference in the mean of expression of MMP-9 between HL and NHL subtypes. Keywords: MMP-9, local invasion, Hodgkin’s lymphoma, Non Hodgkin’s Lymphoma.

Abstract B45: A novel therapeutic approach for neuroblastoma

Abstract Neuroblastoma (NB), a tumor of the primitive neural crest, despite aggressive treatment regimens, portends a poor long-term survival for patients with advanced high stage NB. Here, we investigated the effects of targeting two families of critical regulatory molecules involved in cancer progression, histone deacetylases (HDACs) and carbonic anhydrases (CAs). HDACs regulate the expression and activity of various proteins involved in carcinogenesis and cancer progression, whereas carbonic anhydrases (CAs) function in tumor cell pH homeostasis and therein regulation of growth, survival, and metastasis. In this study we have used HDAC inhibitor (HDACi), pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate (MS-275) and CA inhibitor acetazolamide (AZ). We report that MS-275, at nanomolar concentrations, significantly reduced the tumor initiating cell fraction (TIC) in NB cell lines in reference to NT2/D1, a teratocarcinoma cell line, exhibiting a stem cell like phenotype in-vitro. Stemness genes Oct-5, SOX2 and nanog, assessed by flow cytometry and western blot were found to be significantly down-regulated after MS-275 treatment. Overall, the tumor growth inhibitory effect of MS-275 was demonstrated by cytotoxicity assays, FACs analysis, and “In cell Western” assay. In-vivo treatment with MS-275 (20 mg/Kg) in human NB SH-SY5Y subcutaneous NOD/SCID xenograft model significantly reduced the tumor weight after 21 days treatment compared to the control (AZ 30%; MS-275 85%; AZ+MS-275 90%); (AZ p&amp;lt;0.05; MS-275 and MS-275+AZ p&amp;lt;0.0001). The efficacy of MS-275 was further enhanced by co-administration of AZ (40 mg/Kg) without causing morbidity in mice. Electron microscopy and H&amp;E staining revealed higher numbers of apoptotic cells in MS-275 and AZ+MS-275 treated tumors. Upon re-implantation of tumor cells from primary xenografts in mice, the MS-275+AZ treated cells did not produce palpable tumors after two months whereas untreated cells produced large tumors. This significant reduction in initial tumorigenicity and subsequent abrogation suggests potential elimination of NB tumor initiating cells. Thus MS-275 combined with AZ shows promise as a potent novel anti-NB therapeutic strategy given their current clinical utility. Citation Format: Reza Bayat Mokhtari, Sr., Micky Tsui, Sr., Shamim Lotfi, Sr., Sushil Kumar, Sr., Narges Baluch, Syed S. Islam, Bikul Das, Herman Yeger. A novel therapeutic approach for neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B45.

Mechanisms of recurrence of Ta/T1 bladder cancer

Bladder cancer recurrence occurs via four mechanisms - incomplete resection, tumour cell re-implantation, growth of microscopic tumours, and new tumour formation. The first two mechanisms are influenced by clinicians before and immediately after resection; the remaining mechanisms have the potential to be influenced by chemopreventive agents. However, the relative importance and timing of these mechanisms is currently unknown. Our objective was to postulate the incidence and timing of these mechanisms by investigating the location of bladder cancer recurrences over time. The topographical locations of tumours and their recurrences were analysed retrospectively for 169 patients newly-diagnosed with Ta/T1 bladder cancer, with median follow-up of 33.8 months. Tumours were assigned to one or more of six bladder sectors, and time to recurrence and location of recurrences were recorded. Median time to first tumour recurrence was 40 months. Median times between subsequent recurrences were 6.6, 7.9, 8.0 and 6.6 months for recurrences 1 to 2, 2 to 3, 3 to 4, and 4 to 5, respectively. The risk of first tumour recurrence in any given bladder sector increased by nearly 4-fold if the primary tumour was resected from that sector (P < 0.001); this association was not significant for subsequent recurrences. The proportion of tumour recurrences in multiple bladder sectors increased from 13% for the first recurrence to 100% for recurrence seven onwards. First tumour recurrence appears different to subsequent recurrences; incomplete resection and tumour cell reimplantation may dominate at this time-point. Only later does genuine new tumour formation appear to increase in importance. This has important implications for clinical trials, especially those involving chemopreventive agents.

IMMEDIATE ADMINISTRATION OF INTRAVESICAL MITOMYCIN C AFTER TUMOUR RESECTION FOR SUPERFICIAL BLADDER CANCER

OBJECTIVE To assess the feasibility and safety of administering intravesical mitomycin C in theatre immediately after transurethral resection of bladder tumour (TURBT). PATIENTS AND METHODS A protocol was developed to allow the safe administration of mitomycin C in theatre immediately after TURBT. Over a 32-month period all patients not excluded by the protocol were given mitomycin C in theatre after TURBT, and any adverse events reported. RESULTS In all, 177 instillations were carried out; there were two minor patient-related complications, and no staff-related adverse events. CONCLUSION The immediate administration of mitomycin C in theatre after TURBT is feasible and safe for patients and staff. It provides the earliest and surest prophylaxis against tumour cell re-implantation at TURBT.

Immediate administration of intravesical mitomycin C after tumour resection for superficial bladder cancer

To assess the feasibility and safety of administering intravesical mitomycin C in theatre immediately after transurethral resection of bladder tumour (TURBT). A protocol was developed to allow the safe administration of mitomycin C in theatre immediately after TURBT. Over a 32-month period all patients not excluded by the protocol were given mitomycin C in theatre after TURBT, and any adverse events reported. In all, 177 instillations were carried out; there were two minor patient-related complications, and no staff-related adverse events. The immediate administration of mitomycin C in theatre after TURBT is feasible and safe for patients and staff. It provides the earliest and surest prophylaxis against tumour cell re-implantation at TURBT.

Establishment and characterization of a rectal cancer model in mice: application to cytokine gene therapy.

We established an orthotopic animal model of rectal cancer in mice and applied this model to the study of the antitumor effects of cytokine-assisted tumor vaccine. The CT-26 murine colon adenocarcinoma cells were inoculated into the submucosa of the rectum of the mice to induce the rectal tumor. The tumor growth rate and the survival time of the mice were observed. The cDNA of granulocyte-macrophage colony-stimulating factor (GM-CSF) was transduced to the CT-26 cell line via a retroviral vector, and the therapeutic effects of irradiated GM-CSF secreting tumor vaccine on the rectal tumor were investigated. All the mice implanted with the wild-type tumor cells had tumor growth in the rectum and died. The mean survival time of the mice was 28.9 days. Two doses of irradiated GM-CSF secreting tumor vaccine administered on days 0 and 3 after tumor cell implantation significantly prolonged the survival of the mice with rectal tumor compared with that of the control groups ( P<0.0001). In contrast, no antitumor effect was observed when the treatment with GM-CSF secreting tumor vaccine was delayed to 3 days after tumor cell implantation ( P>0.17). The results suggest that cytokine gene therapy exerts an antitumor effect on small tumors and may be considered as an adjuvant immunotherapy of rectal cancers and prevention of reimplantation of tumor cells disseminated during or following surgery. The orthotopic animal model of the rectal cancer in mice could be applied to the in vivo experimental studies of rectal cancer.

INHIBITION OF BLADDER CARCINOMA CELL ADHESION BY OLIGOPEPTIDE COMBINATIONS IN VITRO AND IN VIVO

A presumed reason for the high recurrence rate of superficial bladder cancer after transurethral tumor resection is the reimplantation of tumor cells. Because tumor cell adhesion to the extracellular matrix is mediated by integrin molecules, we tested specific integrin receptor blocking oligopeptides to prevent this mechanism. An in vitro cell adherence assay with various bladder cancer cell lines and extracellular matrices, including fibronectin, collagen type I, laminin and combinations, was used to analyze the inhibition of tumor cell adhesion by the matrix specific oligopeptides GRGDS, DGEA and EILDV. In therapeutic in vivo experiments the orthotopic murine bladder tumor model MB49 was used. The ability of oligopeptides to interfere with tumor cell adhesion and consecutive tumor outgrowth was evaluated and compared with that of nonspecific peptides, commercially available irrigation fluid and single dose epirubicin chemotherapy. In vitro fibronectin specific oligopeptides showed a concentration dependent inhibition of tumor cell adherence to fibronectin, whereas adhesion to laminin, collagen and combined matrices was not inhibited. In contrast, combinations of integrin receptor blocking oligopeptides were highly active. In vivo local tumor take was not affected by irrigation fluid, nonspecific peptides or monospecific oligopeptides alone, whereas the combination of the 3 oligopeptides effectively inhibited tumor outgrowth. Combining oligopeptides with various specificities significantly inhibited tumor cell adhesion and tumor outgrowth. Application of this principle in a clinical setting may be an effective method for reducing the recurrence rate of superficial bladder cancer.

Inhibition of CT-26 Murine Adenocarcinoma Growth in the Rectum of Mice Treated with Recombinant Human Interleukin-6

In the present study we evaluated the antitumor effects of recombinant human interleukin-6 (rhIL-6), expressed in Chinese hamster ovary cells, in a murine primary tumor model. We showed that treatment with rhIL-6 substantially inhibited the implantation and growth rates of CT-26 adenocarcinoma tumor cells in the rectal submucosa of syngeneic mice. This effect was achieved by injecting rhIL-6 for 7 consecutive days starting 1 day prior to tumor inoculation. No obvious antitumor effect was noted when rhIL-6 injections started 5 days after tumor inoculation. Analysis of the mechanisms by which rhIL-6 exerts its antitumor effects did not reveal a direct antitumor effect on CT-26 tumor cells or the up-regulation of major histocompatibility complex antigens on these cells. However, infiltration of lymphocytes at the tumor site was observed. Increase of carcinoembryonic antigen by IL-6 was clearly seen in human HT-29 colon carcinoma cells. The possible application of these results for adjuvant immunotherapy of selected colorectal patients and prevention of reimplantation of tumor cells disseminated during surgery is discussed.

Bone marrow purging with mafosfamide--a critical survey.

Autologous bone marrow transplantation (ABMT) is increasingly used to consolidate remissions, primarily in hematological disease. Various purging strategies have been developed to minimize the risk of reimplantation of tumor cells with the bone marrow autotransplant. Pharmacological purging with the oxazaphosphorine derivative mafosfamide has been studied extensively, and recent clinical data suggest that purging with mafosfamide may translate into superior remission duration if compared to nonpurged ABMT in acute leukemia. Chemical and experimental data relevant to mafosfamide-purging and clinical results are reviewed, with special emphasis on safety aspects.