Variety Of Other Solid Tumors Research Articles

Assessment of the safety of nivolumab in people living with HIV with advanced cancer on antiretroviral therapy: the AIDS Malignancy Consortium 095 Study.

Although immunotherapy has emerged as a therapeutic strategy for many cancers, there are limited studies establishing the safety and efficacy in people living with HIV (PLWH) and cancer. PLWH and solid tumors or Kaposi sarcoma (KS) receiving antiretroviral therapy and a suppressed HIV viral load received nivolumab at 3mg/kg every 2weeks, in two dose deescalation cohorts stratified by CD4 count (stratum 1: CD4 count > 200/µL and stratum 2: CD4 count 100-199/µL). An expansion cohort of 24 participants with a CD4 count > 200/µL was then enrolled. A total of 36 PLWH received nivolumab, including 15 with KS and 21 with a variety of other solid tumors. None of the first 12 participants had dose-limiting toxicity in both CD4 strata, and five patients (14%) overall had grade 3 or higher immune related adverse events. Objective partial response occurred in nine PLWH and cancer (25%), including in six of 15 with KS (40%; 95% CI, 16.3-64.7). The median duration of response was 9.0months overall and 12.5months in KS. Responses were observed regardless of PDL1 expression. There were no significant changes in CD4 count or HIV viral load. Nivolumab has a safety profile in PLWH similar to HIV-negative subjects with cancer, and also efficacy in KS. Plasma HIV remained suppressed and CD4 counts remained stable during treatment and antiretroviral therapy, indicating no adverse impact on immune function. ClinicalTrials.gov Identifier: NCT02408861.

Abstract 4256: YH012, a novel bispecific anti-HER2 and TROP2 antibody-drug conjugate, exhibits potent antitumor efficacy

Abstract Bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs) are among the most promising and fastest growing classes of next-generation antibody therapeutics for cancer therapy. The strategy of targeting dual tumor-associated antigens (TAAs) with a BsAb offers several advantages, such as improved efficacy due to synergistic effects, increased target cross-linking and internalization, increased tumor cell specificity and reduced side effects in normal tissues. HER2 is an established therapeutic target for approximately 20% of breast cancers, and its overexpression has been observed in a variety of other solid tumors. Trop-2 is another ideal tumor-associated target overexpressed on a wide variety of solid tumors. Co-expression of HER2 and TROP2 has been found in a number of tumors including gastric, colorectal, bladder and breast cancers. Therefore, co-targeting these TAAs using bispecific antibodies has clinical potential. YH012 is a novel first-in-class bispecific antibody-drug conjugate targeting HER2-TROP2 (HER2-TROP2-ADC), which contains a novel fully human bispecific anti-HER2/TROP2 antibody conjugated with Monomethyl auristatin E (MMAE) via a protease-cleavable linker. The anti-HER2/TROP2 BsAb showed increased endocytosis activity compared with its parental mAbs in tumor cells co-expressing HER2/TROP2, whereas the monovalent HER2 or TROP2 antibodies showed reduced internalization. As expected, YH012 showed increased in vitro potency of cell killing compared to the monovalent HER2/TROP2-ADC. These results suggest that YH012 increases the selectivity of payload delivery demonstrating the beneficial effects of targeting dual TAAs using BsAb-ADC. Moreover, YH012 showed robust anti-tumor efficacy in multiple cell line-derived none-small cell lung cancer (NSCLC) and gastric xenografts. Treatment with YH012 showed sustained tumor growth inhibition, which is more pronounced than the effects of the parental mAb-ADCs and monovalent ADCs. These preclinical data suggest that YH012 could potentially benefit patients with tumors co-expressing HER2 and TROP2 through improved drug selectivity and efficacy. Further investigations on the antitumor activity and safety profile of YH012 are ongoing in dogs. Citation Format: Chengzhang Shang, Liu Yang, Jiyong Zhang, Yanfei Han, Zhuolin Li, Zhenyan Han, Jun Li, Ying Meng, Gao An, Hao Yang, Wenqian An, Lei Chen, John Charpentier. YH012, a novel bispecific anti-HER2 and TROP2 antibody-drug conjugate, exhibits potent antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4256.

Pharmacogenomics of 5-fluorouracil in colorectal cancer: review and update.

Colorectal cancer (CRC) is a disease with high morbidity and mortality rates. 5-fluorouracil (5-FU) is the first-line recommended drug for chemotherapy in patients with CRC, and it has a good effect on a variety of other solid tumors as well. Unfortunately, however, due to the emergence of drug resistance the effectiveness of treatment may be greatly reduced. In the past decade, major progress has been made in the field of 5-FU drug resistance in terms of molecular mechanisms, pre-clinical (animal) models and clinical trials. In this article we systematically review and update current knowledge on 5-FU pharmacogenomics related to drug uptake and activation, the expression and activity of target enzymes (DPD, TS and MTHFR) and key signaling pathways in CRC. Furthermore, a summary of drug combination strategies aimed at targeting specific genes and/or pathways to reverse 5-FU resistance is provided. Based on this, we suggest that causal relationships between genes, pathways and drug sensitivity should be systematically considered from a multidimensional perspective. In the design of research methods, emerging technologies such as CRISPR-Cas, TALENS and patient-derived xenograft models should be applied as far as possible to improve the accuracy of clinically relevant results.

PSMA expression on neovasculature of solid tumors.

The use of prostate specific membrane antigen (PSMA) binding agents, labelled with diagnostic and therapeutic radio-isotopes is opening the potential for a new era of personalized management of prostate carcinoma. A wide variety of immunohistochemistry studies have shown PSMA also to be upregulated on the endothelial cells of the neovasculature of a wide variety of other solid tumors where it may facilitate endothelial cell sprouting and invasion through its regulation of lytic proteases that have the ability to cleave the extracellular matrix. Similar to the introduction of PSMA-targeting theranostics in prostate carcinoma, overexpression of PSMA on newly formed tumor vessels may serve as a target for imaging and subsequent treatment of cancer through the use of agents that are capable of blocking PSMA in its function or through PSMA-mediated delivery of chemotherapeutics or radiation agents. In this review, the available data on PSMA expression on tumor neovasculature in human solid tumors assessed by using immunohistochemistry are discussed.

Nintedanib: first global approval.

Nintedanib (Ofev(®)) is an orally available, small, multiple receptor tyrosine kinase inhibitor developed by Boehringer Ingelheim for the treatment of idiopathic pulmonary fibrosis (IPF) and cancer. Nintedanib received its first global approval in the US in October 2014 for the treatment of IPF. Nintedanib has received a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use for the treatment of IPF, and for the second-line treatment in combination with docetaxel of locally advanced, metastatic or locally recurrent non-small cell lung cancer of adenocarcinoma tumour histology. Phase 3 development programmes are also underway for colorectal cancer and ovarian cancer. Phase 2 investigation is being conducted for a variety of other solid tumours, including hepatocellular carcinoma, mesothelioma, prostate cancer, glioblastoma, renal cell carcinoma and endometrial cancer. This article summarizes the milestones in the development of nintedanib leading to this first approval for IPF.

Aberrations in the epidermal growth factor receptor gene in 958 patients with diverse advanced tumors: implications for therapy

Epidermal growth factor receptor (EGFR) mutations are associated with the response to EGFR inhibitors in patients with non-small-cell lung cancer (NSCLC). We sought to investigate EGFR aberrations in patients with diverse advanced cancers. Patients referred to the phase I clinic were evaluated for the presence of EGFR mutations and response to therapy. EGFR aberrations were detected in 34 of 958 patients (3.5%). Though EGFR mutations were most frequent in NSCLC (21 of 131, 16%), they were also present in a variety of other solid tumors (13 of 827 patients, 1.6%) including adrenocortical (1/10 patients), skin (1/24), breast (1/55), carcinoid (1/8), cholangiocarcinoma (1/20), head and neck (1/61), ovarian (1/84), parathyroid (1/1), salivary gland (1/20), renal (1/17), sarcoma (2/38), and thymic carcinomas (1/7). Of the 13 EGFR aberration-positive non-NSCLC patients (median number of prior systemic therapies = 3), 6 had treatment with an EGFR inhibitor. Two patients (diagnosis = parathyroid tumor and basal cell carcinoma) achieved stable disease (SD), lasting 6 and 7 months, respectively. We found EGFR aberrations in 1.6% of a large group of patients with diverse tumors other than NSCLC, and treatment with an EGFR inhibitor could be associated with prolonged SD.

Dabrafenib in the treatment of advanced melanoma

Advanced melanoma has long been a challenging malignancy to treat due to a relative paucity of efficacious therapeutic options. However, the identification of activating BRAF mutations in approximately 50% of patients with cutaneous melanoma has ushered in the era of targeted therapy for melanoma patients. Similar to the first-in-class selective serine/threonine-protein kinase B-raf inhibitor vemurafenib, dabrafenib is highly efficacious in melanoma patients with BRAF V600E mutations, with response rates of approximately 50% and progression-free survival of 6 months. There is data to suggest that dabrafenib not only shows activity in V600E-mutated melanoma, but also in non-V600E BRAF-mutated disease such as V600K. There is also early data to suggest that dabrafenib is effective in controlling metastases in the brain. Combining dabrafenib with the selective mitogen-activated protein kinase kinase (MEK) inhibitor trametinib has been effective in improving both the progression-free survival and overall survival of melanoma patients over those patients treated with dabrafenib alone. Dabrafenib is still being evaluated in several clinical trials in melanoma as well as a variety of other solid tumors with BRAF mutations. The U.S. Food and Drug Administration has recently approved dabrafenib as a single agent for the treatment of unresectable or metastatic melanoma in adult patients with BRAF V600E mutation.

PWE-075 Lack of association between the PSCA rs2294008 polymorphism, or PSCA expression, and colorectal neoplasia

IntroductionProstate stem cell antigen (PSCA) has been implicated in the pathogenesis of several solid tumours, either due to changes in protein expression, or through association with the rs2294008 (C>T) polymorphism...

Functional significance of B7-H1 expressed by human uveal melanoma cells

B7-H1, a recently described B7 family member, has been reported to negatively regulate T-cell function in most cancer cells. In this study, we sought to investigate B7-H1 expression in four uveal melanoma (UM) cells (OCM1, SP6.5, OM431 and VUP) to determine the functional significance of B7-H1 expression in T-cell immune response. Using flow cytometry (FCM), we demonstrated that SP6.5 cells had high B7-H1 protein expression, while the other three UM cell lines had none. However, all four UM cell lines expressed B7-H1 mRNA, as confirmed by reverse transcription-polymerase chain reaction. In co-culture experiments using B7-H1-expressing UM cells with T-cells, FCM to determine CD69 expression in T-cells revealed that SP6.5 cell-related B7-H1 inhibited T-cell activation. This effect was eliminated by B7-H1-targeted RNA interference. An Annexin V/PI double staining assay further showed that B7-H1 expressed by SP6.5 cells did not increase the apoptosis of T-cells, though it was found in a variety of other solid tumors. In conclusion, all the UM cell lines constitutively expressed B7-H1 mRNA, while B7-H1 protein was expressed at different levels. UM-related B7-H1 expression negatively regulated T-cell immune response through the inhibition of T-cell activation, and not through the promotion of T-cell apoptosis. This provides new insight into anti-tumor immunity against B7-H1-expressing UM cells.

Exploratory Study of 99mTc-EC20 Imaging for Identifying Patients with Folate Receptor–Positive Solid Tumors

99mTc-EC20 is a folate receptor (FR)-targeted imaging agent consisting of the vitamin folate conjugated to 99mTc. FR is expressed on a variety of epithelial cancers, with advanced cancers often expressing FR at significantly higher levels than earlier stages of the disease. The goals of this pilot study were to determine the percentages of various solid tumors that accumulate 99mTc-EC20 in vivo and to correlate 99mTc-EC20 uptake with immunohistochemistry (IHC) analysis of FR expression in available biopsied tumor tissue. A total of 154 patients with proven or suspected cancer and at least one lesion of > or =1.5 cm underwent imaging with 99mTc-EC20. The majority of these patients (77%) had a diagnosis of renal cell carcinoma. The remaining patients had a variety of other solid tumors. Whole-body planar images were obtained 1-2 h after injection, followed by SPECT of the region containing index lesions. The uptake of 99mTc-EC20 in tumors was scored as no uptake, mild uptake, or marked uptake. The resultant 99mTc-EC20 data were analyzed for correlation with the expression of the alpha-isoform of FR, as determined by IHC analysis, in tissue available from prior or subsequent surgery or biopsy. The administration of 99mTc-EC20 was well tolerated. Tumors with increased 99mTc-EC20 uptake were identified in 68% of patients, and IHC results were positive for the expression of the alpha-isoform of FR in 67% of patients. The agreement between methods was 61% overall (kappa = 0.096; 95% confidence interval = -0.085 to 0.277), with 72% agreement of positive results and 38% agreement of negative results. In vivo imaging with 99mTc-EC20 identified approximately two thirds of patients as having FR-positive tumors. Agreement between imaging and in vitro IHC was poor but was potentially confounded by a lack of correlation between the time of tissue sampling and the time of 99mTc-EC20 imaging, the heterogeneous expression of FR in metastatic lesions from the same patient, and the inability to detect the beta-isoform of FR by IHC. This pilot study of 99mTc-EC20 scintigraphy indicates that the agent is safe and well tolerated and that this noninvasive procedure may have utility in selecting patients likely to benefit from FR-targeted therapy.

Paclitaxel: a review of adverse toxicities and novel delivery strategies

Better known as Taxol® (Bristol-Myers Squibb), paclitaxel is the first member of the taxane family to be used in cancer chemotherapy. The taxanes exert their cytotoxic effect by arresting mitosis through microtubule stabilization, resulting in cellular apoptosis. The use of paclitaxel as a chemotherapeutic agent has become a broadly accepted option in the treatment of patients with ovarian, breast and non-small cell lung cancers, malignant brain tumors, and a variety of other solid tumors. However, significant toxicities, such as myelosuppression and peripheral neuropathy, limit the effectiveness of paclitaxel-based treatment regimens. This review addresses the toxicities associated with paclitaxel treatment and describes existing and future strategies of paclitaxel administration directed at limiting these toxicities.

Assessment of safety with abbreviated, weight-based bevacizumab infusions in a variety of solid tumors

19674 Background: Bevacizumab (BEV), a humanized monoclonal antibody that neutralizes vascular endothelial growth factor, has shown improved responses in patients with colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) while displaying activity in a variety of other solid tumors. Phase I clinical trials with BEV utilized standard 90- 60-, and 30-minute infusions for 1st, 2nd, and subsequent infusions, as tolerated; initial doses reported less than 3% incidence of infusion-related adverse events (AEs), with 0.2% grade III/IV reactions. Recommended infusion rates for BEV remain unchanged despite the minimal risk of infusion-related AEs. Saltz and colleagues recently reported novel data supporting the safety and tolerability of abbreviated BEV infusions in CRC patients within a single institution. Our objective was to replicate previously reported safety profiles while utilizing abbreviated infusions of BEV in multiple tumor types. Methods: An internal retrospective analysis revealing minimal infusion AEs with standard infusions facilitated this current study. BEV- naïve and previously-treated patients were consented for the study utilizing the following weight-based infusion times: 5, 10, and 15 mg/kg doses over 10, 20, or 30 minutes, respectively, for all doses. Patients were assessed throughout and immediately following the infusion for any infusion-related AE. Results: A variety of tumor types are represented in 26 enrolled patients including CRC, NSCLC, breast, ovarian, pancreatic, and brain. Central nervous system involvement accounted for 35% of patients [primary brain (23%) and metastatic disease (12%)]. A considerable number of patients (19%) were treated with single-agent BEV. Nine BEV-naïve patients were initiated on abbreviated infusions, while 16 were converted from the standard infusion schedule. Seventy-seven total doses utilizing the abbreviated infusions failed to produce infusion-related AEs. Conclusion: These results support previous data affirming the safety and tolerability of abbreviated BEV infusions in CRC patients, while also reporting promising safety of abbreviated infusions in a variety of additionally unreported solid tumors types. No significant financial relationships to disclose.

Tumor Vascular Proteins As Biomarkers in Ovarian Cancer

This study aimed to identify novel ovarian cancer biomarkers and potential therapeutic targets through molecular analysis of tumor vascular cells. Immunohistochemistry-guided laser-capture microdissection and genome-wide transcriptional profiling were used to identify genes that were differentially expressed between vascular cells from human epithelial ovarian cancer and healthy ovaries. Tumor vascular markers (TVMs) were validated through quantitative real-time polymerase chain reaction (qRT-PCR) of immunopurified tumor endothelial cells, in situ hybridization, immunohistochemistry, and Western blot analysis. TVM expression in tumors and noncancerous tissues was assessed by qRT-PCR and was profiled using gene expression data. We identified a tumor vascular cell profile of ovarian cancer that was distinct from the vascular profile of normal ovary and other tumors. We validated 12 novel ovarian TVMs. These were expressed by immunopurified tumor endothelial cells and localized to tumor vasculature. Select TVMs were found to be specifically expressed in ovarian cancer and were absent in all normal tissues tested, including female reproductive tissues with physiologic angiogenesis. Many ovarian TVMs were expressed by a variety of other solid tumors. Finally, overexpression of any one of three ovarian TVMs by vascular cells was associated with decreased disease-free interval (all P < .005). We have identified for the first time the molecular profile of ovarian tumor vasculature. We demonstrate that TVMs may serve as potential biomarkers and molecular targets for ovarian cancer and a variety of other solid tumors.

Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications

Pemetrexed is a new-generation antifolate, approved for the treatment of mesothelioma and non-small cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors. This review traces the history of antifolates that led to the development of pemetrexed and describes the unique properties of this agent that distinguish it from other antifolates. These include (a) its very rapid conversion to active polyglutamate derivatives in cells that build to high levels and are retained for long intervals to achieve prolonged and potent inhibition of its major target enzyme thymidylate synthase, (b) its high affinity for three folate transporters, and (c) its marked sensitivity to the level of physiologic folates in cells. The latter results in the unique and paradoxical finding that when transport mediated by the major folate transporter (the reduced folate carrier) is impaired, pemetrexed activity is preserved. This is due to concurrent contraction of competing cellular physiologic folates and utilization of a novel second transport carrier for which pemetrexed has high affinity, recently identified as the proton-coupled folate transporter (PCFT). Laboratory studies are reviewed that raise the possibility of new approaches to the use of folic acid supplementation in clinical regimens with pemetrexed.

655. Development of a Human Carboxylesterase That Can Efficiently Metabolize CPT-11

CPT-11 is a water-soluble camptothecin analogue that has shown remarkable antitumor activity against a variety of tumors in xenograft models and in clinical trials. It is currently approved for the treatment of advanced colorectal cancers, and is likely to be approved for use against a variety of other solid tumors. CPT-11 is a prodrug that is metabolized in vivo by carboxylesterases (CEs) to generate the potent topoisomeraseI inhibitor, SN-38. Among the highly homologous mammalian CEs, a rabbit liver carboxylesterase (rCE) is the most efficient at CPT-11 activation.

Mapping and characterization of the amplicon near APOA2 in 1q23 in human sarcomas by FISH and array CGH.

BackgroundAmplification of the q21-q23 region on chromosome 1 is frequently found in sarcomas and a variety of other solid tumours. Previous analyses of sarcomas have indicated the presence of at least two separate amplicons within this region, one located in 1q21 and one located near the apolipoprotein A-II (APOA2) gene in 1q23. In this study we have mapped and characterized the amplicon in 1q23 in more detail.ResultsWe have used fluorescence in situ hybridisation (FISH) and microarray-based comparative genomic hybridisation (array CGH) to map and define the borders of the amplicon in 10 sarcomas. A subregion of approximately 800 kb was identified as the core of the amplicon. The amplification patterns of nine possible candidate target genes located to this subregion were determined by Southern blot analysis. The genes activating transcription factor 6 (ATF6) and dual specificity phosphatase 12 (DUSP12) showed the highest level of amplification, and they were also shown to be over-expressed by quantitative real-time reverse transcription PCR (RT-PCR). In general, the level of expression reflected the level of amplification in the different tumours. DUSP12 was expressed significantly higher than ATF6 in a subset of the tumours. In addition, two genes known to be transcriptionally activated by ATF6, glucose-regulated protein 78 kDa and -94 kDa (GRP78 and GRP94), were shown to be over-expressed in the tumours that showed over-expression of ATF6.ConclusionATF6 and DUSP12 seem to be the most likely candidate target genes for the 1q23 amplification in sarcomas. Both genes have possible roles in promoting cell growth, which makes them interesting candidate targets.

Bisphosphonates: clinical experience.

Bone is a preferred site of metastasis for many solid tumors, and the complications associated with bone metastases can result in significant skeletal morbidity including severe bone pain, pathologic fracture, spinal cord compression, and hypercalcemia of malignancy (HCM). Bisphosphonates are the current standard of care for preventing skeletal complications associated with bone metastases. Clinical trials investigating the benefit of bisphosphonate therapy have used a composite end point defined as a skeletal-related event (SRE) or bone event, which typically includes pathologic fracture, spinal cord compression, radiation or surgery to bone, and HCM. Bisphosphonates have been shown to significantly reduce the incidence of these events in patients with bone metastases. Zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ), pamidronate (Aredia; Novartis Pharmaceuticals Corp.), clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), and ibandronate (Bondronat; Hoffmann-La Roche Inc.; Nutley, NJ) all have demonstrated efficacy superior to that of placebo in patients with breast cancer. Zoledronic acid is the only bisphosphonate that has been compared directly with pamidronate, and it was shown by multiple event analysis to be significantly more effective at reducing the risk of an SRE. In patients with prostate cancer, clodronate, etidronate (Didronel; Procter and Gamble Pharmaceuticals, Inc.; Cincinnati, OH), and pamidronate have demonstrated transient palliation of bone pain. However, zoledronic acid is the only bisphosphonate to demonstrate both significant and sustained pain reduction and a significantly lower incidence and longer time to onset of SREs compared with placebo. Zoledronic acid is also the only bisphosphonate to demonstrate efficacy in patients with bone metastases from a variety of other solid tumors, including lung cancer and renal cell carcinoma. In conclusion, bisphosphonates effectively reduce skeletal complications in patients with bone metastases from breast cancer, and zoledronic acid has demonstrated the broadest clinical activity in patients with a wide variety of tumor types.

The role of DNA adduct structure and conformation in cisplatin resistance

Cisplatin belongs to the group of platinum anti-tumour compounds widely used in the treatment of testicular and ovarian cancers and a variety of other solid tumours. The target for cisplatin is DNA, with which it binds efficiently to form a variety of monoadducts and cross-links, either between adjacent bases on the same strand of DNA or on opposing strands. These DNA lesions contribute to the cytotoxicity of cisplatin because they block DNA replication and promote cell death. In addition, several cellular proteins bind preferentially to cisplatin-damaged DNA, which could stimulate transduction pathways and ultimately signal apoptosis.One such protein is MutS, a component of the mismatch repair (MMR) machinery that removes aberrantly inserted bases from newly synthesized DNA following replication. Binding of MutS to cisplatin adducts is thought to result in a continuous, futile cycle of repair on the opposing DNA strand, ultimately leading to cell death. Loss of MMR in tumour cells confers cisplatin resistance, and there has been considerable investigation into the development of platinum compounds for use in cisplatin-resistant disease, and whose cytotoxicity is not circumvented by loss of MMR. Drugs that contain the bulky, non-polar diaminocyclohexane (DACH) ligand in place of the amine ligands of cisplatin appear to be promising in this respect. The DACH ligand, present in drugs such as oxaliplatin, is thought to have a different structural conformation in DNA than the corresponding cisplatin adduct, and perhaps provides a less recognizable structure for MutS.Zdraveski et al. [1xMutS preferentially recognizes cisplatin- over oxaliplatin-modified DNA. Zdraveski, Z.Z. et al. J. Biol. Chem. 2002; 277: 1255–1260Crossref | PubMed | Scopus (75)See all References][1] have investigated this hypothesis by examining the binding of MutS to DNA-containing adducts formed by cisplatin and a DACH analogue. In vitro MutS binding assays revealed that purified MutS bound to cisplatin-modified DNA with twofold greater affinity than DNA modified with the DACH analogue. Sensitivity assays using Escherichia coli mutants corroborate these results; E. coli deficient in methylation, a process essential to MMR that distinguishes between newly synthesized and template DNA strands following replication, were twofold more sensitive to cell death by cisplatin than to DACH analogues. DACH-containing platinum drugs might therefore be less dependent on MMR-mediated cytotoxicity, and exert their cell killing effects by another mechanism, such as replication blockage. Indeed, the equal sensitivity of recombination-deficient mutants to both drugs suggest that the adducts formed by both cisplatin and DACH analogues block replication with equal efficiency.This study adds to the existing evidence that drugs that contain DACH ligands, such as oxaliplatin, might overcome the cisplatin resistance of MMR-deficient tumours. Furthermore, this study demonstrates the importance of structural differences in the structural conformation of DNA adducts formed by cytotoxic drugs, and supports the development of platinum drugs based on their coordination chemistry to combat drug resistance in human tumours.

CD16+ Monocytes in Patients With Cancer: Spontaneous Elevation and Pharmacologic Induction by Recombinant Human Macrophage Colony-Stimulating Factor

The small subset of circulating monocytes that express the maturation-associated CD16 antigen has recently been reported to be elevated in patients with bacterial sepsis. We now show that this novel CD16+ monocyte population is also spontaneously expanded in patients with cancer. We studied 14 patients with metastatic gastrointestinal carcinoma enrolled ina clinical trial of recombinant human macrophage colony-stimulating factor (rhMCSF) plus monoclonal antibody D612. We found that before any cytokine treatment, 12 of 14 patients constitutively displayed significant elevations in both the percentage and the absolute number of CD16+ monocytes, as compared with both normal subjects and ill patients with elevated monocyte counts but without malignancy. CD16+ monocytes accounted for 46% +/- 22% of total monocytes in the patients with cancer versus 5% +/- 3% for controls (P < .01). The increase was not attributable to infection or intercurrent illness and appeared to be associated with the underlying malignancy itself. A similar spontaneous elevation of CD16+ monocytes was observed in 35 of 44 additional patients diagnosed with a variety of other solid tumors. When patients with gastrointestinal carcinoma were treated with rhMCSF, there was a marked further increase in the percentage of CD16+ monocytes (to 83% +/- 11%), as well as in the absolute number of CD16+ cells and the level of CD16 antigen expression. In every case, the patients with cancer showed a greater CD16+ monocyte response than the maximal response obtained in normal volunteer subjects treated witha similar regimen of rhMCSF (n = 5, P < .001), suggesting that the presence of malignancy primed patients for enhanced responsiveness to rhMCSF. We hypothesize that spontaneous expansion of the CD16+ monocyte population may represent a novel biologic marker for a widespread and previously unsuspected host immune response to malignancy.

DNA amplification in human gastric carcinomas

We recently identified a genomic domain at chromosome 10q26 that is highly amplified in the gastric carcinoma cell lines KATO III and SNU-16 and contains the BEK/K-sam gene, which encodes several growth factor receptors. A contiguous segment of 200 kb spanning this gene was amplified in five of 139 (3.6%) primary gastric carcinomas, all of them classified as poorly differentiated tumors. There was no amplification of this genomic region in a variety of other solid tumors. The overall frequency of gene amplification among the gastric carcinomas rose to 19.4% when MYC, ERBB2, and INT2 were included in the analysis, with significant association with advanced tumor stage. Amplification of various genomic regions in solid tumors may be more frequent than previously estimated.