Gastrin-releasing peptide (GRP) induces angiogenesis and the specific GRP blocker 77427 inhibits tumor growth in vitro and in vivo

Angiogenesis is becoming a major target for antitumor therapies, and identifying new angiogenic factors and their specific inhibitors may provide new avenues for tumor management. Here we identify gastrin-releasing peptide (GRP) as a new angiogenic molecule that is secreted by tumors and acts directly upon GRP receptors in the endothelial cells. Addition of GRP increases endothelial cell migration and cord formation in vitro, and induces angiogenesis in an in vivo assay. We have recently identified a small molecule GRP blocker, compound 77427. This inhibitor significantly reduced endothelial cell cord formation in vitro and angiogenesis in vivo. Conversely, when applied to VEGF-induced angiogenesis, the small molecule did not have any effect, demonstrating its specificity. Furthermore, this GRP blocker was able to reduce lung tumor cell growth in vitro as demonstrated by MTT and clonogenic assays. When applied to a xenograft model with lung cancer cells, compound 77427 reduced tumor volume to undetectable sizes, although when the treatment was suspended, tumors began to grow again at normal rates. Our collective observations indicate that GRP is a new angiogenic peptide and that its inhibition offers an attractive tool to reduce tumor burden.     

Genetic determinants of methotrexate responsiveness and resistance in colon cancer cells

Alternative genetic pathways characterized by specific genetic profiles and exhibiting distinctive biological and clinical features have been proposed in colorectal carcinogenesis. Methotrexate (MTX) is a potent inhibitor of the dihydrofolate reductase (DHFR) enzyme, which is essential for DNA synthesis and cell growth. We have evaluated the association between different genetic features and the capacity to develop MTX resistance in colon cancer cell lines representative of alternative genetic pathways. Three aneuploid cell lines (HT-29, SW480, and SK-CO-1) showed pre-existing amplifications, but only one (HT-29) developed MTX resistance, showing amplification of the DHFR gene at 5q12-14 (>20-fold amplification and presence of extrachromosomal double minutes). Failure to develop resistance was attributed to the absence of two complete chromosomes 5 in SW480 and SK-CO-1 cells. Four near-diploid cell lines (LoVo, HCT116, DLD-1 and KM12C) and two aneuploid KM12C-derived metastases (KM12SM and KM12L4A) developed MTX resistance but none exhibited DHFR amplification. All resistant cells without DHFR gene amplification showed microsatellite instability. We conclude that chemoresistance capacity and the mechanism of chemoresistance are related with the genetic pathway and the karyotypic features of colon cancer cells.     

There is no evidence that the SDHB gene is involved in neuroblastoma development

Neuroblastoma and pheochromocytoma have the same embryonal origin. They originate from neural crest cells, and they usually affect suprarenal glands. The SDHB gene encodes the B subunit of succinate dehydrogenase, a protein implicated in the electron transport chain and Krebs cycle. Some mutations have been described in this gene in pheochromocytoma, and this gene could be an appropriate candidate for its study in neuroblastoma given its localization in 1p35-36. The aim of this study was to analyze neuroblastoma tumors in order to assess a possible implication of this gene in neuroblastoma development. We studied 28 neuroblastoma tumor samples from different stages. Mutation research in genomic DNA was carried out after individual amplification of each of the eight SDHB exons by SSCP analysis and sequencing of those samples with migration pattern variants. No variant was found except for three polymorphisms in four neuroblastoma samples. The first polymorphism was a synonymous A-->C change in the third position of codon 6 (exon 1). The other two polymorphisms were a TTC insert at the 5' flanking intron sequence of exon 5 in a stretch of seven TTC repeats. Upon the basis of posterior microsatellite instability and hypermethylation promoter studies, which were not significant, we can conclude that the SDHB gene, a positional candidate gene, is unlikely to be related to either initiation or tumoral progression in neuroblastoma.     

Incidence of leukemias in children from El Salvador and Mexico City between 1996 and 2000: Population-based data

Background

There are very few studies that report the incidence of acute leukemias in children in Latin America. This work assesses the incidence of acute leukemias, between 1996 and 2000, in children from 0–14 years old who were attended at the Mexican Social Security Institute in Mexico City and in children from 0–11 years old in El Salvador.

Methods

Design: Population-based data. Hospitals: In San Salvador, El Salvador, Hospital Nacional de Niños "Benjamín Bloom", the only center in El Salvador which attends all children, younger than 12 years, with oncologic disease. The Pediatric Hospital and the General Hospital of the Mexican Social Security Institute in Mexico City, the only centers in Mexico City which attend all those children with acute leukemia who have a right to this service. Diagnosis: All patients were diagnosed by bone marrow smear and were divided into acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and unspecified leukemias (UL). The annual incidence rate (AIR) and average annual incidence rate (AAIR) were calculated per million children. Cases were stratified by age and assigned to one of four age strata: 1) <1 year; 2) 1–4 years; 3) 5–9 years, or 4) 10–14 or 10–11 years, for Mexico City and El Salvador, respectively.

Results

The number of cases was 375 and 238 in El Salvador and Mexico City, respectively. AAIRs in Mexico City were 44.9, 10.6, 2.5, 0.5, and 58.4 per million children for ALL, AML, CML, UL, and total leukemias, respectively. The AAIRs in El Salvador could not be calculated because the fourth age stratum in El Salvador included children only from 0–11 years old. The incidence rates for the Salvadoran group of 0–11 year olds were 34.2, 7.1, 0.6, 0.2, and 43.2 per million children for ALL, AML, CML, UL, and total leukemias, respectively.

Conclusion

Reported AIRs for each age group in El Salvador were similar to those from other American countries. The AAIR of ALL in Mexico City is one of the highest reported for North America.     

Cyclophosphamide hypersensitivity in a leukemic child

Although hypersensitivity reactions to chemotherapeutic drugs have rarely been reported, they may occur with any of these agents. A Mexican native 44-kg 13-year-old boy suffering from acute lymphoblastic leukemia (ALL) received chemotherapy for 7 years. Three years later, a recurrence of ALL was detected in his right testicle. The patient was scheduled to receive 12 weekly cycles of 50 mg/kg of cyclophosphamide (CPM) as a 1-hour intravenous infusion. The patient did not have any history of drug allergies or any other type of ADR. Immediately after the fourth cycle of CPM, the patient developed itchy, maculopapular rash, sweating, respiratory distress, and anxiety. According to the algorithm developed by Naranjo et al, the ADR was classified as probably secondary to CPM. Skin tests were negative to hypersensitivity to CPM, and a new cycle of CPM was administered. However, the patient developed a similar hypersensitivity reaction to CPM. After an analysis of the clinical course of the ADR and the need to continue the chemotherapeutic treatment with CPM, we decided to desensitize the patient to this drug. Total duration of the procedure was 5 hours and was performed on only 1 occasion. The program of 12 cycles of chemotherapy was successfully completed without any sign or symptom of hypersensitivity to CPM. In conclusion, we have reported a case of hypersensitivity to CPM who was successfully desensitized to CPM.     

Giant retroperitoneal liposarcoma

Liposarcoma is a malignancy of fat cells and is the most frequent soft tissue sarcoma localized in the retroperitoneum. It can reach substantial proportions. It is a slow-growing tumor, and the most frequent symptom is nonspecific abdominal pain and diffuse abdominal enlargement. Treatment is radical surgery and complete resection is essential for local control of the disease. We present a case of giant right retroperitoneal liposarcoma, which was well-encapsulated and could be completely excised. The patient is currently in follow up and at 2 years is disease-free.