Combinations Of Antineoplastic Drugs Research Articles

Dysgeusia increases the risk for death and other side effects during antineoplastic systemic treatment for solid tumors: a cross-sectional study.

Chemotherapy (CT) is a systemic treatment using a combination of antineoplastic drugs, orally or intravenously, that inhibit tumor growth and fast-growing normal cells. Due to its nonspecificity, chemotherapy can cause a series of adverse effects, such as altered taste (dysgeusia), associated with malnutrition and, consequently, other adverse effects in the gastrointestinal tract and increased mortality risk. This study aimed to evaluate the influence of dysgeusia on the incidence of other adverse effects and overall survival during antineoplastic chemotherapy. An observational, retrospective, cross-sectional study was conducted using data from the Electronic Health Record system of the Cancer Institute of Ceará over two years. Before the CT session, the multi-professional team evaluated the patient for the presence and severity of adverse effects (AE), using scores from the CTCAE v5.0 scale. Dysgeusia scores were collected and associated with clinical pathological data, with other adverse effects (nausea, vomiting, diarrhea, oral mucositis, anorexia, constipation), and with overall survival. Chi-square and Mantel-Cox log-rank tests were used. Of 5744 patients evaluated, dysgeusia presented a frequency of 50.6%, being directly associated with female gender (p=0.001), overweight (p=0.022), high tumor stages (p=0.009), a combination of adjuvant and neoadjuvant (p=0.010) and four-year survival (p=0.030). Dysgeusia frequency was directly associated with diarrhea (p<0.001), anorexia (p<0.001), oral mucositis (p<0.001), nausea (p<0.001), constipation (p<0.001) and vomiting (p<0.001), and inversely associated with fatigue (p=0.035). Dysgeusia during CT increases the risk of other adverse effects and negatively impacts prognosis.

Dual Akt and Bcl-2 inhibition induces cell-type specific modulation of apoptotic and autophagic signaling in castration resistant prostate cancer cell lines.

Cancer cell survival depends on the cross-regulation between apoptosis and autophagy which share common signaling pathways including PI3K/Akt/mTOR and Bcl-2. The aim of this study was to elucidate the modulation patterns between apoptosis and autophagy following dual inhibition by Akt inhibitor erufosine and Bcl-2 inhibitor ABT-737 in castration-resistant prostate cancer (CRPC) cell lines, PC-3 (Bax+) and DU-145 (Bax-). Cell cycle progression, apoptotic and autophagic signaling were examined by flow cytometry, multi-caspase assay, Hoechst staining, acridine orange staining of acidic vesicular organelles (AVOs), qRT-PCR and Western Blot. Dual inhibition increased G2/M arrest in PC-3 and DU-145, but not in the healthy prostate epithelium cells, PNT-1A. Only in PC-3, dual inhibition induced synergistic apoptotic and additive autophagic effects. In DU-145 and PNT-1A cells, ABT-737 did not display any remarkable effect on multicaspase activity and erufosine and ABT-737, neither alone nor in combination induced AVOs. By dual inhibition, AKT, BCL-2 and NF-κB gene expressions were downregulated in PC-3, both ATG-5 and BECLIN-1 gene expressions were upregulated in DU-145 but Beclin-1 protein expression was substantially reduced in both CRPC cells. Dual inhibition-induced synergistic multicaspase activation in PC-3 degrades and disrupts autophagic activity of Beclin-1, enhancing caspase-dependent apoptosis. However, in DU-145, following dual inhibition, rate of multicaspase induction and apoptosis are lower but autophagy is completely abolished despite markedly increased BECLIN-1 gene expression. In conclusion, antineoplastic drug combinations may display cell-type specific modulation of apoptotic and autophagic signaling and lack of protective autophagy may not necessarily indicate increased chemotherapeutic sensitivity in heterogenous tumor subpopulations.

A retrospective study on pemetrexed induced nephrotoxicity in non-small cell lung carcinoma patients

Background: Pemetrexed (PEM) is a new-generation multitargeted antifolate agent that has been shown to have broad-spectrum efficacy in a variety of human cancers, including NSCLC and mesothelioma. Dose-limiting hematologic toxicities are among the most serious side effects. PEM nephrotoxicity is well-known, but its occurrence is thought to be rare. Aim was to determine nephrotoxicity induced due to pemetrexed in non-small cell lung cancer patients.Methods: In patients with the NSCLC, we record a retrospective review on PEM- induced renal toxicity. A total of 327 NSCLC patients were treated in our hospital between 2012 and 2019. Of these, 134 patients were diagnosed with 2 or more chemotherapy cycles. 60 of these patients have been diagnosed with combination of antineoplastic drugs based on pemetrexed and platinum. Others were removed from the study and were also required to be tested for other potential causes of renal injury.Results: Suitable statistical tools were used and data was analysed which showed that repeated chemo cycles of pemetrexed leads to the reversible acute kidney injury. With the results from our study we can understand the severity of nephrotoxicity induced with pemetrexed in patients with non-small cell lung cancer. Most of the patients were in the first and second stages of nephrotoxicity and most of them were male. Majority of the patients were also above 40 years of age and also endured more than 4 chemo cycles.Conclusions: It shows that PEM allows longer survival, but acute or chronic kidney failure is the price for this achievement. In conclusion, renal toxicity should be controlled routinely in patients treated with pemetrexed. Before each cycle of pemetrexed, creatinine clearance should be measured. Patients need to be well hydrated during treatment. The patient should also be tested for concomitant medications, and any nephrotoxic symptoms should be reviewed and those drugs removed.

Sequenciamento de infusão de antineoplásicos: contribuições para a prática de enfermagem oncológica baseada em evidência

Este estudo objetivou identificar as evidências científicas disponíveis acerca das interações medicamentosas entre antineoplásicos decorrentes da ordem de infusão para, então, descrever a melhor sequência de aplicação e discutir sua aplicabilidade na Sistematização da Assistência de Enfermagem (SAE). Revisão integrativa da literatura operacionalizada em 2018 nas bases MEDLINE, LILACS, CINAHL e BVS, a partir dos termos Neoplasms, Drug Therapy, Drug Interactions, Chemotherapy e Sequence Administration. Foram analisados 57 estudos que, em conjunto, estudaram 40 combinações de antineoplásicos, apontando as interações farmacocinéticas e farmacodinâmicas decorrentes da ordem de infusão, as quais subsidiaram a construção de um quadro determinando o melhor sequenciamento para cada uma dessas combinações. Um fluxograma também foi produzido para, junto com o quadro, apoiar a SAE na perspectiva da prática de enfermagem oncológica baseada em evidência. Selecionar as sequências de infusão de antineoplásicos combinados representa nova estratégia conceitual para enfermeiros que administram protocolos de poliquimioterapia.

Leucemia linfoblástica en el embarazo

Acute Leukemia occurs mainly in age groups of children under 5 years and in elderly patients, however; can also be seen in women of reproductive age. The prevalence of adult acute leukemia in young pregnant women is very rare, one case in 75,000 pregnancies and only 28% of them correspond to Lymphoblastic Leukemia occurs. The association between Acute Lymphocytic Leukemia and pregnancy poses a complex situation where you should not take or delay treatment, but the use of antineoplastic drug combinations often requires discontinuation of prenatal period. The case of a patient described here in the second trimester of pregnancy diagnosed with Acute Lymphoblastic Leukemia common B, treated with the protocol Modified Berlin. Gestation was developed successfully and cesarean section at 33 weeks was performed, a girl is born with good vitality, mother and daughter are currently healthy and stay in control.

Toxins from the Caribbean sea anemone Bunodeopsis globulifera increase cisplatin-induced cytotoxicity of lung adenocarcinoma cells

BackgroundLung cancer causes 1.4 million deaths worldwide while non-small-cell lung cancer (NSCLC) represents 80-85% of the cases. Cisplatin is a standard chemotherapy against this type of cancer; however, tumor cell resistance to this drug limits its efficacy. Sea anemones produce compounds with pharmacological activities that may be useful for augmenting cisplatin efficacy. This study aimed to evaluate the pharmacological activities of crude venom (CV) from the sea anemone Bunodeopsis globulifera and four derived fractions (F1, F2, F3 and F4) to test their increase efficiency cisplatin cytotoxicity in human lung adenocarcinoma cells.ResultsPre-exposure to CV, F1 and F2 fractions increases cisplatin cytotoxicity in human lung adenocarcinoma cells under specific conditions. Exposure to CV at 50 μgmL-1 induced a reduction of approximately 50% in cell viability, while a similar cytotoxic effect was observed when cell culture was exposed to F1 at 25 μgmL -1 or F2 at 50 μgmL-1. The cell culture exposure to F1 (10 μgmL-1) fraction combined with cisplatine (25 μM) provoked a decrease in MTT reduction until 65.57% while F2 (25 μgmL-1) fraction combined with cisplatin (10 μM) provoked a decrease in MTT reduction of 72.55%.ConclusionsThe F1 fraction had the greatest effect on the lung adenocarcinoma cell line compared with CV and F2. The combination of antineoplastic drugs and sea anemone toxins might allow a reduction of chemotherapeutic doses and thus mitigate side effects.

Combinations of Plant Polyphenols &amp; Anti-Cancer Molecules: A Novel Treatment Strategy for Cancer Chemotherapy

The investigation of chemotherapeutic agents for the treatment of cancer since the early 1940s has resulted in the discovery of over 50 drugs till date. However, most of these drugs result in severe side effects causing physical and mental trauma to patients. In order to eliminate the side effects, search for better and safer drugs has been ongoing for several decades, which has resulted in the discovery of anti-cancer properties of many phytochemicals. Polyphenols represent a unique class of phytochemicals that possess excellent anti- oxidant, anti-inflammatory properties and also modulate cell signalling pathways leading to anti-cancer effects. However, the use of these compounds as anti-cancer agents is not as effective and hence combinations of chemotherapeutic drugs with these molecules have been attempted. Promising results in in vitro and in vivo experiments while using combinations of polyphenols and chemotherapeutic agents open up new avenues for the discovery of the ideal drug combinations for cancer therapy. This review highlights the efficacy of the combination of phytochemicals with synthetic anti � neoplastic drugs over the conventional combinations of anti-neoplastic drugs and the possible interventions in the clinical settings. The review also discusses the inclusion of polyphenols in emerging therapeutic modalities like nanotechnology and photodynamic therapy.

Impact of combinations of antineoplastic drugs on intestinal microflora in 9 patients with leukaemia.

The impact of antineoplastic drugs on the intestinal microflora was studied in 9 patients with acute leukaemia during chemotherapy and in 5 patients also during chemotherapy-induced neutropenia. Quantitative and qualitative microbiological analyses of faecal samples obtained before and during chemotherapy showed significantly increased counts of Bacteroides spp. in 3/9 patients and, during neutropenia, significantly increased counts of yeasts in 2/5 patients; however, the intestinal microflora was stable in most patients.

Second-Line Chemotherapy with Cisplatin-Ifosfamide in Patients with Ovarian Cancer Previously Treated with Carboplatin-Cyclophosphamide

In an effort to use antineoplastic drug combinations which are active in platinum resistant ovarian cancer or which can induce a second response after a platinum first-line treatment, we conducted a study on 30 ovarian cancer patients previously treated with carboplatin plus cyclophosphamide who were given ifosfamide 5 g/m2 i.v. divided over days 1 to 3 plus mesma combined with cisplatin 100 mg/m2 i.v. divided over days 1 to 3 every 4 weeks as second-line treatment. Eight patients had never entered remission with first-line chemotherapy while 22 patients had tumor recurrence within 6 to 18 months after the end of chemotherapy and their tumors were considered potentially platinum sensitive. Responding patients received 6 courses while palliative treatment for nonresponders was provided. Of the 22 patients with tumor recurrence, 8 patients responded with one partial response (PR) and 7 complete clinical responses (CCR). Two out of the 8 patients with platinum resistant disease demonstrated short lasting PR. Seven patients with CCR underwent second-look operation and in two a pathological CR was documented. Median time to progression was 6 mo (4-12). The median overall survival was 12 mo (4-20). Myelotoxicity despite G-CSF administration was significant with grade 4 leukopenia in 40% and grade 3 thrombocytopenia in 20% of patients. Central nervous system (CNS) toxicity was significant with 30% somnolence, 20% disorientation and an episode of grand-mal epilepsy ascribed to ifosfamide. With a 33% response rate the combination is as effective as new agents employed in relapsed ovarian cancer. Platinum-refractory disease may respond to a lesser degree. The most important determinant of response was the progression-free interval from first-line chemotherapy. Whether patients recurring after carboplatin plus cyclophosphamide have a greater chance to respond to cisplatin plus ifosfamide or vice-versa cannot be supported by the current data and therefore randomized studies should be performed to this end.

Apoptosis May Be Either Suppressed or Enhanced with Strategic Combinations of Antineoplastic Drugs or Anti-IgM

A variety of drugs have been used to treat B-lymphocyte neoplasms, including both cell cycle-specific (CCS) and non-cell-cycle-specific drugs. Although the therapy for such cancers is complex and can include both types of drugs, the efficacy of these drugs in inducing cell death remains unclear. In this paper we have concentrated on specific CCS drugs and have examined their ability to induce programmed cell death (apoptosis) in Burkitt's lymphoma cell lines derived from patients. The CCS drugs chosen were hydroxyurea and aphidicolin (active in late G1, early S phase), the topoisomerase poisons camptothecin and etoposide (S, early G2phase) and vincristine and Taxol (late G2, M phase). These choices allow comparison of two drugs with differing modes of action for each of the various phases of the cell cycle. Our results indicate that the variation in apoptosis between drugs that act at the same phase of the cell cycle is negligible. Both S/G2and G2/M blockers are very potent at inducing apoptosis whereas G1/S blockers are ineffective in the induction of apoptosis. In addition, marked kinetic variations in the rate of apoptosis induction were observed, etoposide and camptothecin being more rapid in their action than the other agents. The order of effectiveness in inducing apoptosis on a kinetic basis was S/G2agents ⪢ G2/M agents ⪢ G1/S agents. In this study we have also found that growth inhibition was induced by all the CCS agents chosen and by anti-IgM in various Burkitt's lymphoma lines. Furthermore c-mycwas down-regulated under similar conditions. Since apoptosis was only selectively induced by some of the CCS agents, it implies c-mycexpression is associated with growth regulation and c-myc down-regulation is an insufficient condition for the induction of apoptosis. In addition, cotreatments using the CCS and other agents revealed the following: Cotreatment using two CCS drugs which act at the same stage in the cell cycle showed either no change or only additivity to the effects seen with either agent alone. However, cotreatment with CCS drugs showed that an inhibitory effect is found between G1/S and G2/M drugs or S/G2and G2/M drugs. No effect was found between G1/S and S/G2drugs. Anti-IgM, which by itself was capable of inducing apoptosis, was observed to augment apoptosis induced by very low concentrations of G2/M-acting drugs but it has little effect on G1/S or the S/G2drugs. The inhibitory effect of anti-CD40 or TNF-α on anti-IgM-induced apoptosis did not carry over to an effect on apoptosis induction by the CCS agents. Thus specific combinations of agents may lead to either enhancement, inhibition, or no interactive effect on apoptosis.

Amifostine for protection from antineoplastic drug toxicity.

The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of amifostine are reviewed. Amifostine is a prodrug converted by alkaline phosphatase to the active sulfhydryl compound WR-1065. WR-1065 protects normal cells by scavenging free radicals, donating hydrogen ions to free radicals, depleting oxygen, and binding to active derivatives of antineoplastic agents. The immediate conversion of amifostine to WR-1065, its small volume of distribution, and the limited amount of drug and metabolite recovered in the urine suggest that amifostine is rapidly dephosphorylated and enters cells as its active metabolite. The selectivity of amifostine for normal tissue is hypothesized to be a results of the decreased vascularity of tumors, decreased activity of alkaline phosphatase in tumor cells, and pH dependence of WR-1065 uptake. In clinical studies, amifostine decreased the frequency of cisplatin-induced nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression. Amifostine has demonstrated an ability to decrease the hematologic toxicity of cyclophosphamide, carboplatin, mitomycin, and antineoplastic drug combinations. Amifostine has FDA-approved labeling for use in reducing cumulative renal toxicity in patients receiving repeat doses of cisplatin for advanced ovarian cancer and non-small-cell lung cancer. The recommended dose in adults is 910 mg/m2 administered as a 15-minute infusion 30 minutes before the start of chemotherapy. The major adverse effects of amifostine include hypotension and emesis. The benefits of amifostine must be weighted against its potential adverse effects, and the drug's impact on the efficacy of antineoplastics should be further investigated. Amifostine has shown promise in protecting non-malignant cells from the toxic effects of antineoplastics, apparently without compromising toxicity against cancer cells.

Evaluation of toxicity and efficacy of a combination of antineoplastic agents in the prevention of PVR.

The retinal toxicity of a combination of antineoplastic drugs in free and liposome-encapsulated form was determined in the rabbit eye. Bleomycin sulfate and 5-fluorouridine were evaluated by clinical observation, electroretinogram, and histological study. Forty-five eyes were injected with combinations of various doses of bleomycin and 5-FUR in free and encapsulated form; 10 eyes served as controls. The nontoxic free dose was found to be 3.5 micrograms bleomycin and 150 micrograms 5-FUR. Liposome encapsulation increased the nontoxic dose to 4.7 micrograms bleomycin and 200 micrograms 5-FUR. Four groups of rabbits in which proliferative vitreoretinopathy had been induced were used for the efficacy study; the control group received an injection of PBS; the second group was injected with a combination of 3.5 micrograms bleomycin and 150 micrograms 5-FUR in free form; the third group was injected with the identical doses in liposome-encapsulated form; and the fourth group received encapsulated bleomycin (4.7 micrograms) and 5-FUR (200 micrograms). The dose used in Group 4 was significantly more effective (P < 0.01) in preventing tractional retinal detachment and marginally more effective (P = 0.054) in preventing neovascularization.

Relationships between various uses of antineoplastic drug-interaction terms.

In in vitro testing, no pharmacologic synergism has been found for the combination of cisplatin and etoposide in P388 leukemia in contrast to the demonstration of therapeutic synergism in the same model. No pharmacologic synergism has been found for the same combination in the treatment of four small-cell lung-cancer cell lines, although clinical results obtained using this combination in small-cell lung cancer and other cancers suggest a therapeutic advantage. The popular concept of synergy, implying a therapeutic advantage, is different from the pharmacologic meaning, which generally implies that less drug is required in a combination for an equal effect. Therapeutic advantage may be obtained regardless of whether drugs are synergistic in the pharmacologic sense in the treatment of a tumor. To gain a more comprehensive insight into concepts of drug interaction, it is important to recognize that the type of drug interaction seen is dependent on the drug doses used and may vary with the treatment of different cell lines. All of these factors complicate the use of the word synergism, or any associated term, in a categorical manner to describe the effects of combinations of antineoplastic drugs.

Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children's Research Hospital experience, 1962 to 1988.

To gauge the impact of intensified therapy on the survival of infants (younger than 1 year, n = 129) and children (greater than or equal to 1 year of age, n = 275) with neuroblastoma, we analyzed the results of eight successive clinical trials comparing various combinations of antineoplastic drugs, surgery, and radiotherapy. Changes in treatment did not affect the survival of children with involved noncontiguous lymph nodes or distant metastatic disease until the combination of cisplatin and teniposide (CDDP/VM26) was added to a basic regimen of cyclophosphamide and doxorubicin (CTX/DOX). The resulting 4-year survival was 28% +/- 5% (SE) compared with 7% +/- 2% for previous treatments (P less than .001 by the log-rank test). The 4-year survival of infants with metastatic disease was improved by administering CTX/DOX to all patients, reserving CDDP/VM26 for those whose disease was resistant to the former combination: 82% +/- 6% versus 45% +/- 8% in earlier studies; P less than .001. In the subset of infants whose tumors had disseminated to bone or bone marrow at diagnosis, this therapeutic approach increased the probability of long-term survival from 48% +/- 10% to 85% +/- 9% (P = .01). The small group of children over 1 year of age with localized unresectable tumors also fared significantly better with the switch to CTX/DOX chemotherapy (4-year survival, 93% +/- 7% v 42% +/- 13%; P = .02). Multivariate analysis indicated that young age, limited-disease stage, nonadrenal primary site, and intensified treatment were independent predictors of a more favorable outcome. We conclude that substantial advances in the treatment of neuroblastoma have occurred over the past 25 years at this institution. The current overall 4-year survival probability of 57% +/- 4% compares favorably with estimates for most other common solid tumors of childhood.