Toxic Side Effects Of Chemotherapy Research Articles

Using Drosophila melanogaster to identify chemotherapy toxicity genes.

The severity of the toxic side effects of chemotherapy shows a great deal of interindividual variability, and much of this variation is likely genetically based. Simple DNA tests predictive of toxic side effects could revolutionize the way chemotherapy is carried out. Due to the challenges in identifying polymorphisms that affect toxicity in humans, we use Drosophila fecundity following oral exposure to carboplatin, gemcitabine and mitomycin C as a model system to identify naturally occurring DNA variants predictive of toxicity. We use the Drosophila Synthetic Population Resource (DSPR), a panel of recombinant inbred lines derived from a multiparent advanced intercross, to map quantitative trait loci affecting chemotoxicity. We identify two QTL each for carboplatin and gemcitabine toxicity and none for mitomycin. One QTL is associated with fly orthologs of a priori human carboplatin candidate genes ABCC2 and MSH2, and a second QTL is associated with fly orthologs of human gemcitabine candidate genes RRM2 and RRM2B. The third, a carboplatin QTL, is associated with a posteriori human orthologs from solute carrier family 7A, INPP4A&B, and NALCN. The fourth, a gemcitabine QTL that also affects methotrexate toxicity, is associated with human ortholog GPx4. Mapped QTL each explain a significant fraction of variation in toxicity, yet individual SNPs and transposable elements in the candidate gene regions fail to singly explain QTL peaks. Furthermore, estimates of founder haplotype effects are consistent with genes harboring several segregating functional alleles. We find little evidence for nonsynonymous SNPs explaining mapped QTL; thus it seems likely that standing variation in toxicity is due to regulatory alleles.

Role of herbals in cancer management

Herbal medicines have a vital role in the prevention and treatment of cancer. A great deal of pharmaceutical research done in technologically advanced countries like USA, Germany, France, Japan and China has considerably improved quality of the herbal medicines used in the treatment of cancer. With advanced knowledge of molecular science and refinement in isolation & structure elucidation techniques, we are in a much better position to identify various anticancer herbs and develop the remedy that might cure cancer. The therapeutic effect of anticancer herbs is executed by inhibiting cancer-activating enzymes, stimulating DNA repair mechanism, promoting production of protective enzymes, inducing antioxidant action and by enhancing activity of the immune cells. Some herbs protect the body from cancer by enhancing detoxification functions of the body. Certain biological response modifiers derived from herbs are known to inhibit growth of cancer by modulating the activity of specific hormones and enzymes. Some herbs reduce toxic side effects of chemotherapy and radiotherapy. Scientists all over the world are concentrating on the herbal medicines to boost immune cells of the body against cancer. By understanding the complex synergistic interaction of various constituents of anticancer herbs, the herbal formulations can be designed to attack the cancerous cells without harming normal cells of the body.

The Genetic Architecture of Methotrexate Toxicity Is Similar in Drosophila melanogaster and Humans

The severity of the toxic side effects of chemotherapy varies among patients, and much of this variation is likely genetically based. Here, we use the model system Drosophila melanogaster to genetically dissect the toxicity of methotrexate (MTX), a drug used primarily to treat childhood acute lymphoblastic leukemia and rheumatoid arthritis. We use the Drosophila Synthetic Population Resource, a panel of recombinant inbred lines derived from a multiparent advanced intercross, and quantify MTX toxicity as a reduction in female fecundity. We identify three quantitative trait loci (QTL) affecting MTX toxicity; two colocalize with the fly orthologs of human genes believed to mediate MTX toxicity and one is a novel MTX toxicity gene with a human ortholog. A fourth suggestive QTL spans a centromere. Local single-marker association scans of candidate gene exons fail to implicate amino acid variants as the causative single-nucleotide polymorphisms, and we therefore hypothesize the causative variation is regulatory. In addition, the effects at our mapped QTL do not conform to a simple biallelic pattern, suggesting multiple causative factors underlie the QTL mapping results. Consistent with this observation, no single single-nucleotide polymorphism located in or near a candidate gene can explain the QTL mapping signal. Overall, our results validate D. melanogaster as a model for uncovering the genetic basis of chemotoxicity and suggest the genetic basis of MTX toxicity is due to a handful of genes each harboring multiple segregating regulatory factors.

Cytotoxic Effects of Chemotherapeutic Drugs and Heterocyclic Compounds at Application on the Cells of Primary Culture of Neuroepithelium Tumors

Neuroepithelial tumor cells were cultured in vitro. The biopsy material was taken from 93 children at removal of the brain tumors during neurosurgical operations. The individual features of the cells sensitivity of primary cultures in respect to protocol-approved chemotherapy drugs and changes in the Interleukin-6 (Il-6) level in the culture medium after the application of chemotherapy were established. The initial level of Il-6 exceeded 600.0 pg/ml in the cultural medium with histologically verified pilomyxoid astrocytoma cells, and ranged from 100.0 to 200.0 pg/ml in the medium at cultivation of ganglioneuroblastoma and pilocytic astrocytoma. A decrease in the Il-6 level in the medium culture of primary tumors cells was observed after the application of chemotherapeutic agents on the cells of pilomyxoid astrocytoma, astrocytomas, and pilocytic desmoplastic/nodular medulloblastoma. The production of Il-6 increased after application of cytostatic drugs on the cells of oligoastrocytomas. A decrease in Il-6 level after application of Cisplatin and Methotrexate and a 5-10 fold increase in the level of Il-6 after application of Etoposide, Carboplatin, Cytarabine, and Gemcitabine were registered in the medium with ganglioneuroblastoma. To improve the cytotoxic action of chemotherapeutic agents, the combined application of cytostatics with heterocyclic compounds was carried out. A computer modeling of ligand-protein complexes of carbamide using the Dock 6.4 and USF Chimera program packages was performed with molecular mechanics method. Special attention was drawn to the ability of several isoxazole heterocycles and isothiazolyl to inhibit the tyrosine kinase. It was proved in vitro that the joint application of chemotherapeutic agents and heterocyclic compounds could reduce the concentration of the cytostatic factor by 10 or more times, having maintained the maximum cytotoxic effect. It was assumed that the target amplification of cytotoxic action of chemotherapeutic agents had prospects for reducing toxic side effects of chemotherapy in vivo, which would be carried out only after the preclinical studies.

Role of KCNMA1gene in breast cancer invasion and metastasis to brain

BackgroundThe prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, large-conductance calcium- and voltage-activated potassium channel (BKCa) channels are significantly upregulated in breast cancer cells. In this study we investigated the role of KCNMA1 gene that encodes for the pore-forming α-subunit of BKCa channels in breast cancer metastasis and invasion.MethodsWe performed Global exon array to study the expression of KCNMA1 in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of BKCa channel protein in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells (MCF-10A), non-metastatic breast cancer (MCF-7), non-brain metastatic breast cancer cells (MDA-MB-231), and brain-specific metastatic breast cancer cells (MDA-MB-361) to study whether BKCa channel inhibition attenuates breast tumor invasion and metastasis using KCNMA1 knockdown with siRNA and biochemical inhibition with Iberiotoxin (IBTX).ResultsThe Global exon array and RT-PCR showed higher KCNMA1 expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased BKCa channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking KCNMA1.ConclusionDetermining the relative abundance of BKCa channel expression in breast cancer metastatic to brain and the mechanism of its action in brain metastasis will provide a unique opportunity to identify and differentiate between low grade breast tumors that are at high risk for metastasis from those at low risk for metastasis. This distinction would in turn allow for the appropriate and efficient application of effective treatments while sparing patients with low risk for metastasis from the toxic side effects of chemotherapy.

Role of KCNMA1 gene in breast cancer invasion and metastasis to brain.

Abstract Abstract #2043 Background: The prognosis for patients with brain metastasis from breast cancer is extremely poor. A significant number of breast tumor patients despite aggressive therapy develop metastatic disease in brain. The mechanism or the cause of breast cancer metastasis to brain is unknown. Therefore, it is critical to identify prognostic molecular markers of the metastatic process in order to design therapeutic modalities for reducing the occurrence of metastasis. In this study we investigated KCNMA1 gene, which encodes alpha subunit of calcium activated potassium (KCa) channels. Altered KCa channels, are described in a wide variety of tumor cell types and up-regulation of KCa channels was shown to be a novel mechanism for the malignant phenotype of human tumor cells.
 Material and Methods: We performed Global GeneChip exon arrays to study the expression of KCNMA1 gene in metastatic breast cancer in brain and compared it with primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immuno-histochemistry was performed to study the expression and localization of alpha subunit of KCa channel protein in primary and metastatic breast tumor tissues and breast cancer cell lines. We performed Matrigel invasion, transendothelial migration and membrane potential assays in normal breast cells (MCF-10A), non-metastatic breast cancer (MCF-7), non-brain metastatic breast cancer cells (MDA-MB-231), and brain-specific metastatic breast cancer cells (MDA-MB-361) to study whether KCa channel inhibition attenuates breast tumor invasion and metastasis to brain.
 Results: The Global GeneChip exon array and RT-PCR showed higher KCNMA1 gene expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased KCa channel activity, leading to greater invasion and trans-endothelial migration, which could be attenuated by blocking the KCNMA1 gene with siRNA and biochemical inhibition with IBTX.
 Discussion: Recent investigations in patients with metastatic lung and breast cancers reported alarming rates of brain metastases. Unraveling the genetic aberrations that drive the metastatic events in these cancer cells offer insights into how to limit or prevent this lethal process. For instance, determining the relative abundance of KCNMA1 gene in breast cancer metastasis to brain and understanding the mechanism of brain metastasis provides a unique opportunity to identify specific genetic markers that could differentiate between low grade breast tumors that are at high risk for metastasis from those at low risk for metastasis. This would in turn allow for the appropriate and efficient application of treatments to obtain the greatest benefit while sparing low risk patients for metastasis from the toxic side effects of chemotherapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2043.

BARRIERS TO GENETIC-BASED MEDICINE

IMAGINE THAT RESEARCHERS have discovered a genetic biomarker in some breast tumors that can help predict whether a woman will have a recurrence of breast cancer and, therefore, whether chemotherapy will be effective. Women who test positive for the biomarker would receive chemotherapy regardless of their other risk factors, and women who test negative would not. Such a treatment approach could save thousands of lives while sparing some women from the toxic side effects of chemotherapy. The situation is hypothetical, but it is one that oncologists and other physicians are grappling with as genetic testing and personalized medicine become more mainstream. Two key issues have emerged from the debate over genetic-based health care. The first is the concern over patient privacy as more and more genetic data are generated and shared over the Internet. The second is the clamor for the Food & Drug Administration to regulate genetic tests to ensure that they measure what ...

Cytotoxic conjugates of peptide hormones for cancer chemotherapy

A major problem in traditional cancer treatment is the severe toxic side effects of chemotherapy. One approach to increasing drug specificity revolves around the receptors for certain peptide hormones that are aberrantly expressed in many human cancers and peritumoral vessels feeding tumors. This allows some peptides, when used as cytotoxin delivery vectors, to yield conjugates with specific therapeutic advantages, such as rapid tumor cell internalization and tumor-penetrating ability. Thus, peptides can be conjugated with cytotoxic agents which would concentrate in tumor tissue and/or cells through specific peptide-receptor interactions. Overall, this relatively new approach to chemotherapy effectively increases the specificity and efficacy of the cytotoxic agent and should decrease toxic side effects. Peptide hormones such as somatostatin (SST), bombesin (BN), luteinizing hormonereleasing hormone (LHRH) or their analogues have been used as drug delivery vectors when linked with various cytotoxic agents, such as camptothecin (CPT), paclitaxel (PTX) and doxorubicin (DOX). Several lead cytotoxic peptide conjugates have been developed and demonstrate greater cytotoxicity against various cancers together with reduced toxicity to normal tissues. Two examples, JF-10-81 and AN-152, are currently undergoing preclinical and clinical development, respectively. These new cytotoxic peptide conjugates may provide more effective chemotherapy and drug delivery protocols for receptor-specific cancer treatment in the near future.

Polymorphisms in the MGMT Gene as Predictors of Leukemia Risk and Response to Therapy in Children with AML.

Approximately 40% of patients treated with chemotherapy for pediatric AML will relapse after initial treatment and 8–10% will die of toxic side effects of chemotherapy. This highly variable response to standardized treatment protocols is due in part to genetic variation among patients in the metabolism of chemotherapeutic agents and in the response to the DNA damage they induce. We have analyzed polymorphisms in the coding region of the DNA alkylation repair gene O6-Methylguanine-DNA Methyltransferase (MGMT) in 356 patients with de novo pediatric AML to determine whether naturally occurring MGMT variant alleles correlate with leukemia susceptibility, treatment efficacy, and the incidence of adverse effects of chemotherapy. The polymorphism rs2308321 (Ile143Val) has been shown to modify biochemical properties of the MGMT protein, with altered substrate specificity of the rare valine allele (G genotype) compared with the isoleucine allele (A genotype) (Margison et al, Carcinogenesis , 26;1473, 2005). All patients were treated on Children's Cancer Group protocols 2941 and 2961. Outcomes were examined stratified by genotype. All patients received intensively timed induction therapy with IDA-DCTER (idarubicin, dexamethasone, Ara-C, thioguanine, etoposide and daunomycin) given on days 0 to 3 followed by DCTER given on days 10 to 13. On recovery of ANC and platelet counts, patients were randomized to consolidation therapy with a further course of IDA-DCTER/DCTER or IDA-FLAG (idarubicin, fludarabine, Ara-C and G-CSF). Patients received intensification with a single course of high dose Ara-C and L-asparaginase unless a family donor was available when allogeneic transplant was performed after busulfan and cyclophosphamide. Black children were significantly more likely to have a homozygous wild-type AA genotype than white children (p=0.002). When compared to a healthy control population, there was no correlation between MGMT polymorphisms and the risk of AML overall. However, in a case-case comparison of genetic sub-types of AML, children with a variant allele (AG or G/G genotype) were significantly more likely to have monosomy 7 than AA cases (9% vs 1%; p=0.01); in contrast, children with trisomy 8 were significantly more likely to have an AA genotype (8% vs 0%; p=0.028). The presence of at least one G allele was associated with a significant reduction in the incidence of relapse. There was no effect on treatment-related mortality (TRM). In a multivariate Cox model adjusted for race, the increased risk of relapse (RR) associated with the variant G allele remained significant (hazard ratio 1.72 95% CI 1.03–2.86; p=0.037). These results suggest that genotyping at the rs2308321 polymorphism in the MGMT gene could be useful in the risk stratification of patients with AML prior to therapy.A/AA/G+G/GN% ± 2 SEN% ± 2 SEp-value5yr OS from end of course 128054 ± 67671 ± 110.0315yr RR from end of course 128043 ± 67627 ± 110.0145yr TRM from end of course 128014 ± 47614 ± 80.11

Induction of an Antitumoral Immune Response by Wild-Type Adeno-Associated Virus Type 2 in an In Vivo Model of Pancreatic Carcinoma

We analyzed the immunologic impact of adeno-associated virus type 2 (AAV-2), a small single-stranded parvovirus with tumorsuppressive properties, on DSL6A pancreatic carcinoma in syngeneic rats. Established tumors of animals treated with AAV-2 or mock infected were resected (Ro), and DSL6A cells were rechallenged on the different site. Eleven (92%) of 12 mock-infected animals but only 3 (25%) of 12 AAV-2-treated animals redeveloped tumors. Adeno-associated virus type 2 infection provoked systemic raises in monocytes and neutrophils numbers and in levels of the proinflammatory monocyte chemoattractant protein 1 and interleukin 10. Adeno-associated virus type 2-treated tumors were infiltrated with monocytes, macrophages, natural killer cells, CD4+ T cells, and especially CD8+ T cells. In cytotoxicity assays, AAV-2-infected DSL6A tumor cells were recognized by lymphocytes from AAV-2-treated animals and from controls. Yet, uninfected DSL6A cells were exclusively killed by lymphocytes from AAV-2-treated animals. Additionally, those lymphocytes displayed high natural killer cell activity but failed to attack unrelated tumor targets. Taken together, these results suggest that the antiviral response toward AAV-2 cross-activates the immune system toward simultaneously present tumor disease. This and the known potential to significantly reduce toxic side effects of chemotherapy make nonpathogenic viruses such as AAV-2 as "1-agent combination therapy" to an interesting treatment option of residual tumor disease.

Orexigenic and cytoprotective effects of a novel adenosine-enriched peptide nucleic acid compound: Implications for clinical application

14154 Background: There is a major unmet need for new non-toxic orexigenic and cytoprotective agents that can ameliorate intractable symptoms in cancer such as anorexia, poor wound healing/ulcerations and poor QoL. Underlying causes of these clinical problems include excessive inflammatory/cytokine responses to either treatment related or tumor related processes, or to both at once. AVR118, a novel remarkably non-toxic peptide/nucleic acid formulation has been shown in many anecdotal reports and in small clinical trials, to stimulate appetite, improve fatigue, and assist in more rapidly reversing toxic side effects of chemotherapy, radiation and interferon therapy. It has now been re-characterized to better explain these multiple effects. It binds to adenosine receptors in vitro and increases cAMP release in HEK293 cell lines expressing A2 receptors, mechanistically involving targeted receptor binding, most likely in the gut and in the functional pathway of orexin A. Methodologies: HPLC, co-chromatography with standards, UV and mass spectrometry. Receptor binding/functional assays in vitro, animal models for anti-inflammatory and wound healing studies. Results: AVR 118 consists of a mix of 14 nucleoside derivatives, including available adenosine at a concentration of 2.1mM in stable solution. Also present is a complex aggregate of peptides showing high proline and tyrosine content. AVR 118 binds to adenosine receptors in vitro and increases cAMP release in HEK293 cell lines containing A2 receptors and enhances smooth muscle relaxation mediated by A2 and others such as NK2 and NTS1 in vitro. AVR 118 shows 20% enhancement of epithelialization when compared to saline controls in a controlled porcine wound healing model. Conclusions: AVR 118 may prove to play a major role in palliation of anorexia symptoms associated with serious debilitating diseases such as cancer or AIDS and as adjunctive therapy for these patients. [Table: see text] No significant financial relationships to disclose.

Can less be more for p53?

The tumour-suppressor protein p53 is often mutated in cancer. But it seems that p53 deficiency is not all bad, and inhibiting this protein might mitigate toxic side effects of chemotherapy and radiotherapy. The protein p53 is an important mediator of the DNA damage response and tumour suppression in vertebrates. In general, these two attributes are thought to be causally linked: p53 suppresses tumours by responding to DNA damage or genome abnormalities in tumour cells and triggering growth arrest or apoptosis. Now using a reversibly switchable endogenous p53 mouse model, Christophorou et al. show that the pathological p53-induced response to irradiation is irrelevant to p53-mediated suppression of tumours induced by that irradiation. Conversely, restoring p53 at later times avoids the pathological effects of irradiation but provides much of the tumour suppression. These data suggest that the DNA damage response and tumour suppression are unlinked activities of p53, each induced by distinct signals. A similar conclusion is drawn from a separate experiment, the absence of the tumour suppressor protein ARF was found to abolish the extra cancer-protective activity of an additional copy of p53 in mice. Again, this suggests that oncogenic signalling is critical for triggering protection by p53, whereas activation of p53 as a result of DNA damage has a lesser impact on the final development of tumours. In News and Views, Anton Berns looks at the implications of these findings for models of p53 activity.

Risk factors for development of symptoms after autologous transplantation for multiple myeloma

Background: Multiple myeloma (MM) is the most common indication for autografting in the United States. Although safe, autografting can be associated with substantial morbidity due to the toxic side effects of chemotherapy. Strategies aimed at minimizing symptoms post autografting may result in better tolerance. The risk factors for symptom development post autografting for MM have not been well characterized. Purpose: To define pretransplant conditions, which may be predictive of post-transplant symptom burden.

Risk Factors for Development of Symptoms Post Autologous Transplant for Multiple Myeloma.

Background: Multiple myeloma (MM) is the most common indication for autografting in the United States. Although safe, autografting can be associated with substantial morbidity due to the toxic side effects of chemotherapy. Strategies aimed at minimizing symptoms post autografting may result in better tolerance. The risk factors for symptom development post autografting for MM have not been well characterized.Purpose: To define pretransplant conditions which may be predictive of post-transplant symptom burden.Methods: We performed prospective evaluation of symptom burden among 64 myeloma patients undergoing autograft at MDACC as well as retrospective review of pretransplant variables including patient demographics, performance status, albumin, disease status, and Charlson Comorbidity Index (CCI). Univariate analysis was performed to correlate pretransplant variables with posttransplant symptom burden as defined by M.D. Anderson Symptom Inventory (MDASI) scores at different timepoints post transplant.Results: 64 patients were studied from 6/2000 to 5/2003. Patient characteristics are summarized in Table 1. Symptom burden increased from baseline to day 0 to nadir, with most patients returning to their baseline by day 30 post transplant (Figure 1). Table 2 summarizes the potential impact of pre-transplant variables on median MDASI scores at nadir. Patients with the highest MDASI scores at baseline had the highest MDASI scores at nadir in quartile analysis(p=.001). Patients with Charlson score of ≥ 3, age > 60, β 2M > 3, albumin ≤ 4, and female gender had a trend towards higher nadir MDASI scores. Other pre-transplant variables, including Durie-Salmon stage, LDH, hemoglobin, disease status at time of autograft, and time from diagnosis to autograft had no apparent correllation with symptom burden throughout transplant (data not shown).Conclusions: Autografting for MM is associated with significant but reversible symptom burden during the first 30 days of the procedure. Baseline symptom burden is the most important predictor of post transplant symptom burden. Other potential predictors include Charlson score, age, β 2M, albumin, and female gender. The MDASI scoring system is a potentially useful means of following symptom burden post autografting that could be used to assess interventions aimed at reducing transplant related morbidity in MM patients.Patient CharacteristicsMedian (range)Age at transplantation, years55.2 (30–74)Time to SCT, months7.5 (2.5–73.3)Albumin at transplantation3.74 (2.9–4.5)β2M at transplantation3.79 (1.4–19.3)Charlson score at transplantation3.48 (2–6)Disease status at transplantationn (%)First remission42 (65.6)Primary refractory14 (21.9)Other8 (13.6)Preparative regimenn (%)Melphalan53 (82.8)Other11 (17.2)Male to female ratio1.5 : 1Impact of Pre-transplant Variables on Nadir MDASI ScoresnMedian(range)Charlson score< 35022 (1–97)≥ 31441 (3–72).09Age≤ 60 years4323 (1–97)> 60 years2131 (3–72).2β 2M≤3.03420 (1–85)> 3.02728 (4–97).2Albumin≤ 4.05027 (1–97)> 4.01419 (1–16).2GenderFemale2630 (5–85)Male3823 (1–97).2 [Display omitted]

Autologous soluble tumor-associated antigens prevent the toxic side effects of cancer chemotherapy and inhibit the progress of tumorigenesis: Case report

In this communication, we report for the first time, that immunization of cancer patients with autologous soluble tumor-associated antigens (sTAA) isolated from their own serum prevents the toxic side effects of chemotherapy, improves the patients' clinical status, and has therapeutic effects without chemotherapy. In 2001 and 2002, two cancer patients were treated, during chemotherapy, with autologous sTAA. Another benign tumor-bearing patient was treated with a medicinal herb and autologous sTAA. Doses for subcutaneous injections varied between 2.5 and 3 mg of sTAA in 0.5 ml of sterile distilled water. Injections were performed twice a week or at weekly intervals. In each case, the clinical status of the patient became more stable and healthier. Toxic side effects caused by chemotherapy decreased or even disappeared. No additional toxic side effects were observed after vaccination with sTAA. In the studied cases, a polyp disappeared and a metastatic brain tumor began to encapsulate. No metastases were seen in the case with colon adenocarcinoma. We concluded that vaccination of patients with autologous sTAA prevents the toxic side effects of chemotherapy in cancer patients and improves their clinical status. In the case with the benign tumor, this vaccination activated the host's immune system, prevented progress of the disease and even promoted tumor disappearance. We suggest that immunotherapy with autologous sTAA provides significant clinical benefits in cancer patients and appears to be an important new adjuvant treatment of cancer.

Clinical observation on effect of Shenqi Fuzheng injection combined with chemotherapy in treating post-operational patients with colorectal carcinoma

Chemotherapy (CT) is the most important therapeutic means in treating post-operational patients with colorectal carcinoma (CA) , but its efficacy is often affected by the toxic side-effects of CT agents. TCM could reinforce body resistance and tonify the qi, alleviate the toxic side-effects of CT, thus strengthening the efficacy of organism against tumor. Shenqi Fuzheng ( ~ ~ JE, SQFZ) injection manufactured by Limin Pharmaceutical Factory of Livzon Group was used in treating 69 patients with post-operational colorectal CA in the surgical department of our hospital from October, 1999 to September, 2000, and with the simple CT group of 63 cases as the control. The difference of reaction during the period of CT and the 2-year relapse rate after therapy was observed and is now reported as follows.

Quality of Life Assessment in Patients with Hormone–Resistant Prostate Cancer Treated with Epirubicin or with Epirubicin plus Medroxy Progesterone Acetate – Is It Feasible?

Objectives: The optimal palliative treatment in patients with advanced hormone–resistant prostate cancer (AHRPC) is still under investigation. We studied the effect of epirubicin, alone or combined with medroxy progesterone acetate (MPA), in this particular patient group. The aim of the study was to investigate the feasibility of quality of life (QOL) measurement and to ascertain whether MPA added to epirubicin produces a better QOL than epirubicin alone.Methods: Of 28 randomized patients with symptomatic AHRPC, 26 were eligible for the study. Fourteen of them received epirubicin (100 mg/m² i.v.) every 3 weeks in combination with an oral dose of 500 mg of MPA twice daily. Twelve patients received epirubicin alone. For the QOL assessment, the Rotterdam Symptom Checkliste was used. Toxic side effects of chemotherapy were assed by the WHO criteria. Subjective responses included performance status and pain score.Results: Compliance in completing QOL questionnaires was high (87.5%). In none of the QOL domains studied did any of the patients, irrespective of their treatment, experience an improvement in their QOL. Moreover, after 12 and 24 weeks, patients in both treatment arms experienced a significant worsening of physical symptom distress when compared to study entry. Toxicity was moderate to severe. A biochemical response (drop in prostate–specific antigen of more than 50%) was observed in 5 out of 26 patients (19.1%) and a subjective response in 7 out of 26 patients (26.9%). The median survival for all patients was 30 weeks. There was no statistically significant difference between the two arms. Performance status and the global QOL as judged by the patients themselves were associated with the duration of survival. No relation was found between the initial observed subjective response and survival.Conclusions: The feasibility of measuring QOL in patients with symptomatic AHRPC is demonstrated in the present study. Subjective and biochemical responses were observed in both treatment arms, but these were not translatable as improved measured QOL domains.

Cytokine efficiency in the treatment of high-grade malignant non-Hodgkin's lymphomas: Results of a randomized double-blind placebo-controlled study with intensified COP-BLAM ± rhGM-CSF

In high-grade malignant non-Hodgkin's lymphomas (hNHL) recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was evaluated as support to chemotherapy. In a phase III trial, 172 patients (age 18-73 years, stage II-IV) were risk-stratified according to LDH levels and lymphoma size and randomized to receive rhGM-CSF (400 micrograms) (87 patients) or placebo (85 patients) subcutaneously days 8-14 of each cycle of an intensified COP-BLAM regimen. RhGM-CSF significantly reduced the length and nadir of neutropenia, the length of fever episodes, the frequency of all and of severe infections, and of hospitalization and antibiotic requirements. Complete response rates were 63% for all patients and 64% vs. 61% (n.s.) in the rhGM-CSF vs. the control group. Deviations from protocol in applied dosages of myelotoxic drugs and in cycle intervals maintained differed slightly in favor of the rhGM-CSF arm. However, there were no significant differences in overall survival between the GM-CSF treatment and control groups (21 vs. 23 months). Early relapse rates were markedly lower than in the standard-dose COP-BLAM/IMVP-16 regimen. Thus, GM-CSF abates toxic side effects of chemotherapy and may help to maintain dose intensity in high-risk hNHL.

Stimulation of Pancreas and Gastric Carcinoma Cell Growth by Interleukin 3 and Granulocyte-Macrophage Colony—Stimulating Factor

Hematopoietic growth factors have recently been well characterized by complementary DNA cloning. For human epidermal growth factor, granulocyte-macrophage colony-stimulating factor recombinant proteins have been expressed in Escherichia coli. To reduce the toxic side effects of chemotherapy on the bone marrow, recombinant human granulocyte-macrophage colony-stimulating factor and recombinant human interleukin 3 were applied to patients suffering of gastrointestinal cancers. To determine the influence of recombinant human granulocyte-macrophage colony-stimulating factor and recombinant human interleukin 3 on human pancreas and gastric cancer cell cells in vitro, a sensitive microculture test system was established that allows precise quantification of proliferation. A more than twofold enhancement of proliferation was observed by interleukin 3 and granulocyte-macrophage colony-stimulating factor in two of two cell cultures derived from gastric carcinoma cells, while two of nine cultures from pancreas carcinoma cells have shown enhanced cell growth in the presence of recombinant human interleukin 3 or recombinant human granulocyte-macrophage colony-stimulating factor. In comparison, recombinant human epidermal growth factor increased cell growth in two of two gastric and in five of nine pancreas carcinoma cultures. In general, 1-10 ng/mL of the growth factors yielded the highest growth rate, but even 1-pg amounts produced increased cell growth. Expression of messenger RNA for granulocyte-macrophage colony-stimulating factor, interleukin 3, and the oncogene HER2/neu remained undetectable in all of the tested cell lines, while the various abundance of messenger RNA for the epidermal growth factor receptor was different in each cell line. The reported results imply that the hematopoietic growth factors interleukin 3 and granulocyte-macrophage colony-stimulating factor influence cellular growth of pancreas and gastric carcinoma cells by a paracrine mechanism and may possess a more general regulatory function than originally anticipated.

Stimulation of pancreas and gastric carcinoma cell growth by interleukin 3 and granulocyte-macrophage colony-stimulating factor

Hematopoietic growth factors have recently been well characterized by complementary DNA cloning. For human epidermal growth factor, granulocytemacrophage colony-stimulating factor recombinant proteins have been expressed in Escherichia coli. To reduce the toxic side effects of chemotherapy on the bone marrow, recombinant human granulocyte-macrophage colony-stimulating factor and recombinant human interleukin 3 were applied to patients suffering of gastrointestinal cancers. To determine the influence of recombinant human granulocyte-macrophage colony-stimulating factor and recombinant human interleukin 3 on human pancreas and gastric cancer cell cells in vitro, a sensitive microculture test system was established that allows precise quantification of proliferation. A more than twofold enhancement of proliferation was observed by interleukin 3 and granulocyte-macrophage colony-stimulating factor in two of two cell cultures derived from gastric carcinoma cells, while two of nine cultures from pancreas carcinoma cells have shown enhanced cell growth in the presence of recombinant human interleukin 3 or recombinant human granulocyte-macrophage colony-stimulating factor. In comparison, recombinant human epidermal growth factor increased cell growth in two of two gastric and in five of nine pancreas carcinoma cultures. In general, 1–10 ng/mL of the growth factors yielded the highest growth rate, but even 1-pg amounts produced increased cell growth. Expression of messenger RNA for granulocyte-macrophage colony-stimulating factor, interleukin 3, and the oncogene HER2/neu remained undetectable in all of the tested cell lines, while the various abundance of messenger RNA for the epidermal growth factor receptor was different in each cell line. The reported results imply that the hematopoietic growth factors interleukin 3 and granulocyte-macrophage colony-stimulating factor influence cellular growth of pancreas and gastric carcinoma cells by a paracrine mechanism and may possess a more general regulatory function than originally anticipated.