Showing papers on "Doxorubicin published in 1999"
TL;DR: The potential role of DNA synthesis inhibition, free radical formation and lipid peroxidation, DNA binding and alkylation, DNA cross-linking, interference with DNA strand separation and helicase activity, direct membrane effects, and the initiation of DNA damage via the inhibition of topoisomerase II in the interaction of these drugs with the tumor cell are addressed.
2,118 citations
Journal Article•
TL;DR: In this paper, the maximum tolerated dose, toxicity profile, and pharmacokinetics of doxorubicin were determined as an infusion every 3 weeks to patients with refractory or resistant cancers.
Abstract: PK1 comprises doxorubicin covalently bound to N -(2-hydroxypropyl)methacrylamide copolymer by a peptidyl linker. Following cellular uptake via pinocytosis, the linker is cleaved by lysosomal enzymes, allowing intratumoral drug release. Radically altered plasma and tumor pharmacokinetics, compared to free doxorubicin, and significant activity in animal tumors have been demonstrated preclinically. We aimed to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of PK1 as an i.v. infusion every 3 weeks to patients with refractory or resistant cancers. Altogether, 100 cycles were administered (range, 20–320 mg/m 2 doxorubicin-equivalent) to 36 patients (20 males and 16 females) with a mean age of 58.3 years (age range, 34–72 years). The maximum tolerated dose was 320 mg/m 2 , and the dose-limiting toxicities were febrile neutropenia and mucositis. No congestive cardiac failure was seen despite individual cumulative doses up to 1680 mg/m 2 . Other anthracycline-like toxicities were attenuated. Pharmacokinetically, PK1 has a distribution t 1/2 of 1.8 h and an elimination t 1/2 averaging 93 h. 131 I-labeled PK1 imaging suggests PK1 is taken up by some tumors. Responses (two partial and two minor responses) were seen in four patients with NSCLC, colorectal cancer, and anthracycline-resistant breast cancer. PK1 demonstrated antitumor activity in refractory cancers, no polymer-related toxicity, and proof of principle that polymer-drug conjugation decreases doxorubicin dose-limiting toxicities. The recommended Phase II dose is 280 mg/m 2 every 3 weeks. Studies are planned in colorectal, NSCLC, and breast cancer patients.
739 citations
TL;DR: It is shown here that SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites, which enhances tumorigenicity and confers resistance to chemotherapeutic agents as a result of β1 integrin-stimulated tyrosine kinase activation suppressing chemotherapy-induced apoptosis.
Abstract: Resistance to chemotherapy is a principal problem in the treatment of small cell lung cancer (SCLC). We show here that SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites. Adhesion of SCLC cells to ECM enhances tumorigenicity and confers resistance to chemotherapeutic agents as a result of beta1 integrin-stimulated tyrosine kinase activation suppressing chemotherapy-induced apoptosis. SCLC may create a specialized microenvironment, and the survival of cells bound to ECM could explain the partial responses and local recurrence of SCLC often seen clinically after chemotherapy. Strategies based on blocking beta1 integrin-mediated survival signals may represent a new therapeutic approach to improve the response to chemotherapy in SCLC.
714 citations
Journal Article•
TL;DR: Few breast cell lines are sensitive to TRAIL-induced apoptosis, and no difference in sensitivity is found between normal and malignant cell lines.
Abstract: Expression and function of the TRAIL apoptotic pathway was investigated in normal and malignant breast epithelial cells. Glutathione-S-transferase (GST)-TRAIL extracellular domain fusion proteins were produced to analyze TRAIL-induced apoptosis. Only GST-TRAIL constructs containing regions homologous to the Fas self-association and ligand binding domains could induce apoptosis. GST-TRAIL induced significant (>90%) apoptosis in just one of eight normal and one of eight malignant breast cell lines. All other lines were relatively resistant to TRAIL-induced apoptosis. Activating TRAIL receptors DR4 and DR5 were expressed in all normal and malignant breast cell lines. The inhibitory receptor TRID was highly expressed in one of four normal and two of seven malignant breast cell lines. DR4, DR5, or TRID expression did not correlate with sensitivity to TRAIL-induced apoptosis. Incubation of cell lines with doxorubicin or 5-fluorouracil significantly augmented TRAIL-induced apoptosis in most breast cell lines. By fractional inhibition analysis, the toxicity of the combination of TRAIL and doxorubicin or 5-fluorouracil was synergistic compared with either agent alone. In contrast, melphalan and paclitaxel augmented TRAIL-induced apoptosis in few cell lines, and methotrexate did not augment it in any cell line. Augmentation of TRAIL-induced apoptosis by doxorubicin or 5-fluorouracil was mediated through caspase activation. This was evidenced by the fact that chemotherapy agents that synergized with TRAIL (e.g., doxorubicin) themselves caused cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and their toxicity was blocked by the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2 (ZVAD-fmk). The combination of TRAIL and doxorubicin caused significantly greater caspase-3 and PARP cleavage, and the combined toxicity also was inhibited by ZVAD-fmk. In contrast, chemotherapy agents that did not augment TRAIL-induced apoptosis (e.g., methotrexate) caused minimal caspase-3 and PARP cleavage by themselves, and their toxicity was not inhibited by ZVAD-fmk. These drugs also did not increase caspase-3 or PARP cleavage when combined with TRAIL. In summary, few breast cell lines are sensitive to TRAIL-induced apoptosis, and no difference in sensitivity is found between normal and malignant cell lines. Treatment with chemotherapy provides an approach to sensitize breast cancer cells to TRAIL-induced apoptosis.
591 citations
TL;DR: It is demonstrated that for advanced soft tissue sarcoma, response to chemotherapy is not predicted by the same factors as is overall survival time and needs to be taken into account in the interpretation of trials assessing the value of new agents for this disease on the basis of response to treatment.
Abstract: PURPOSE: A total of 2,185 patients with advanced soft tissue sarcomas who had been treated in seven clinical trials investigating the use of doxorubicin- or epirubicin-containing regimens as first-line chemotherapy were studied in this prognostic-factor analysis. PATIENTS AND METHODS: Overall survival time (median, 51 weeks) and response to chemotherapy (26% complete response or partial response) were the two end points. The cofactors were sex; age; performance status; prior therapies; the presence of locoregional or recurrent disease; lung, liver, and bone metastases at the time of entry onto the trial; long time period between the initial diagnosis of sarcoma and entry onto the study; and histologic type and grade. RESULTS: Univariate analyses showed (a) a significant, favorable influence of good performance status, young age, and absence of liver metastases on both survival time and response rate, (b) a significant, favorable influence of low histopathologic disease grade on survival time, despite a si...
494 citations
TL;DR: In cardiomyocytes cell injury by H2O2 and doxorubicin is limited by an increase in prostacyclin formation that reflects induction of COX-2 mediated by ERK1/2 activation, and the injury was prevented by iloprost, a stable prostacyClin analogue.
377 citations
TL;DR: It is demonstrated that MCF-7 human breast cancer cells in vitro are more susceptible to doxorubicin toxicity at pH 7.4, compared to pH 6.8, the first in vivo demonstration of this important phenomenon.
Abstract: The extracellular (interstitial) pH (pHe) of solid tumours is significantly more acidic compared to normal tissues. In-vitro, low pH reduces the uptake of weakly basic chemotherapeutic drugs and, hence, reduces their cytotoxicity. This phenomenon has been postulated to contribute to a ‘physiological’ resistance to weakly basic drugs in vivo. Doxorubicin is a weak base chemotherapeutic agent that is commonly used in combination chemotherapy to clinically treat breast cancers. This report demonstrates that MCF-7 human breast cancer cells in vitro are more susceptible to doxorubicin toxicity at pH 7.4, compared to pH 6.8. Furthermore 31P-magnetic resonance spectroscopy (MRS) has shown that the pHe of MCF-7 human breast cancer xenografts can be effectively and significantly raised with sodium bicarbonate in drinking water. The bicarbonate-induced extracellular alkalinization leads to significant improvements in the therapeutic effectiveness of doxorubicin against MCF-7 xenografts in vivo. Although physiological resistance to weakly basic chemotherapeutics is well-documented in vitro and in theory, these data represent the first in vivo demonstration of this important phenomenon. © 1999 Cancer Research Campaign
300 citations
TL;DR: The relationship between the structure of Pluronic block copolymers and their biological response modifying effects in MDR cells is useful for determining formulations with maximal efficacy with respect to MDR tumors.
Abstract: Purpose. Previous studies have demonstrated that Pluronic block copolymers hypersensitize multiple drug resistant (MDR) cancer cells, drastically increasing the cytotoxic effects of anthracyclines and other anticancer cytotoxics in these cells. This work evaluates the dose dependent effects of these polymers on (i) doxorubicin (Dox) cytotoxicity and (ii) cellular accumulation of P-glycoprotein probe, rhodamine 123 (R123) in MDR cancer cells.
296 citations
TL;DR: New cytotoxic analogs of LHRH, AN-207 which consists of 2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity binding and are much less toxic and more effective in vivo than their respective radicals in inhibiting tumor growth in L HRH receptor-positive models of human ovarian, mammary, or prostatic cancer.
Abstract: In view of non-specific toxicity of most chemotherapeutic agents against normal cells, the development of targeted chemotherapy is warranted. Efficient targeting of chemotherapeutic drugs to the cancerous area could be of great benefit for patients with advanced or metastatic tumors. Targeted cytotoxic peptide conjugates are hybrid molecules composed of a peptide carrier which binds to receptors on tumors and a cytotoxic moiety. New cytotoxic analogs of LHRH, AN-152 in which doxorubicin (DOX) is linked to [d-Lys(6)]LHRH, and AN-207 which consists of 2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity binding and are much less toxic and more effective in vivo than their respective radicals in inhibiting tumor growth in LHRH receptor-positive models of human ovarian, mammary, or prostatic cancer. These results suggest that targeted cytotoxic LHRH analogs such as AN-207 could be considered for treatment of these cancers. The presence of receptors for bombesin-like peptides on a wide variety of tumors prompted us to use some of our bombesin/gastrin-releasing peptide antagonists as carrier molecules. Cytotoxic bombesin analogs, such as AN-215 containing AN-201, might find application in the treatment of small cell lung carcinoma (SCLC), and colorectal, gastric, pancreatic, mammary, and prostatic cancers. Since somatostatin receptors are found in various human neoplasms and the receptor subtypes to which octapeptide analogs bind with high affinity have been identified, we synthesized several cytotoxic somatostatin analogs including AN-162 and AN-238 containing DOX and 2-pyrrolino-DOX respectively, linked to octapeptide RC-121. Cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of human breast or prostate cancers expressing somatostatin receptors-2 and -5 and can be used for receptor-targeted chemotherapy. Cytotoxic somatostatin analogs might also find applications for the therapy of human pancreatic, colorectal, and gastric cancer as well as brain tumors and non-SCLC. Cytotoxic compounds linked to analogs of hormonal peptides like LHRH, bombesin, and somatostatin that can be targeted to certain tumors possessing receptors for those peptides could be an important addition to oncological armamentarium.
283 citations
TL;DR: The experiments on in vivo tumour models have confirmed high efficacy of SP1049C against drug-resistant tumours, as well as suggested that this product has considerably broader efficacy than doxorubicin.
271 citations
TL;DR: The BR96-doxorubicin immunoconjugate has limited clinical antitumor activity in metastatic breast cancer, and gastrointestinal toxicities likely represent binding of the agent to normal tissues expressing the target antigen and may have compromised the delivery of the immunconjugate to the tumor sites.
Abstract: PURPOSE: BMS-182248-1 (BR96-doxorubicin immunoconjugate) is a chimeric human/mouse monoclonal antibody linked to approximately eight doxorubicin molecules. The antibody is directed against the Lewis-Y antigen, which is expressed on 75% of all breast cancers but is limited in expression on normal tissues. Preclinical xenograft models demonstrated significant antitumor activity, including cures. A randomized phase II design was chosen to estimate the activity of the BR96-doxorubicin conjugate in metastatic breast cancer in a study population with confirmed sensitivity to single-agent doxorubicin. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer and immunohistochemical evidence of Lewis-Y expression on their tumor received either BR96-doxorubicin conjugate 700 mg/m2 IV over 24 hours or doxorubicin 60 mg/m2 every 3 weeks. Patients were stratified on the basis of prior doxorubicin exposure, visceral disease, and institution. Cross-over to the opposite treatment arm was allowed with progr...
Journal Article•
TL;DR: Although both liposomal groups were better than the free drug group in terms of clinically relevant parameters, including toxicity, tumor shrinkage, and survival, there was no difference between the twoliposomal drug groups.
Abstract: Sterically stabilized liposome is characterized by a surface coating of polyethylene glycol (PEG) or other polymers that can reduce opsonization of the liposome by plasma proteins. It has a higher plasma area under the concentration-time curve (AUC), which is believed to correlate with better therapeutic efficacy. However, the presence of large molecules on the liposomal surface may reduce the interactions of liposomes with cells and hinder entry of liposomes into the tumor tissue. Using a stable liposomal system composed of distearoyl phosphatidylcholine/cholesterol, we examined the effect of PEG (Mr 2000) on the pharmacokinetics and on the efficacy of liposomal doxorubicin with C-26 syngeneic tumor model in BALB/c mice. The plasma AUC of liposomal doxorubicin with 6 mol-% PEG-modified distearoyl phosphatidylethanolamine (PEG-DSPE) was approximately twice that of liposomal doxorubicin without PEG at various dosages, regardless of whether the mice were tumor-bearing. Paradoxically, the group of mice treated with liposomal doxorubicin without PEG had higher tumor doxorubicin concentrations. The 72-h tumor AUC was 1.44 times that of liposomal doxorubicin with 6% PEG-DSPE. The tumor-accumulation efficiency (AUC(Tumor)/AUC(Plasma)) of liposomal doxorubicin without PEG was 0.87, and this was more than twice that of the liposomal doxorubicin with 6% PEG-DSPE (0.31). At a dose of 10 mg/kg, although both liposomal groups were better than the free drug group in terms of clinically relevant parameters, including toxicity, tumor shrinkage, and survival, there was no difference between the two liposomal drug groups. In this stable liposome system, surface coating with PEG offered no benefit for liposomal doxorubicin in the C-26 tumor model. To enhance the therapeutic index of liposomal doxorubicin, simply increasing plasma AUC by surface coating with PEG may not be satisfactory.
Journal Article•
TL;DR: It is demonstrated, for the first time, that MDR1 gene expression can be rapidly activated in human tumors after transient in vivo exposure to cytotoxic chemotherapy.
Abstract: Overexpression of P-glycoprotein (Pgp), a multidrug transporter encoded by the MDR1 gene, is associated with chemoresistance in some human solid tumor malignancies. To date, analyses of MDR1 levels in solid tumors have examined constitutive increases in expression at relapse. In the present study, we have evaluated the acute induction of MDR1 gene expression in a solid human tumor as a function of time in response to in vivo exposure to chemotherapy. Five patients with unresectable sarcoma pulmonary metastases underwent isolated single lung perfusion with doxorubicin. Relative MDR1 gene expression was measured in metastatic tumor nodules and normal lung specimens after initiation of chemoperfusion. In four of five patients, a 3-15-fold (median, 6.8) increase in MDR1 RNA levels was detected in tumors at 50 min after administration of doxorubicin. In contrast, normal lung samples had very low levels of MDR1 RNA prior to perfusion, and no acute increases were observed after therapy. These findings demonstrate, for the first time, that MDR1 gene expression can be rapidly activated in human tumors after transient in vivo exposure to cytotoxic chemotherapy.
Journal Article•
TL;DR: Histology indicated that some chambers lacked viable tumor cells at the end of the two week observation period, lending strong support that neutralization of VEGF in combination with conventional cytotoxic agents could be a new innovative treatment regimen for metastatic breast cancer.
Abstract: In the present study, we evaluated the effects of a neutralizing anti-Vascular Endothelial Growth Factor (VEGF) mAb, A4.6.1(200 micrograms twice weekly, i.p.), on angiogenesis and growth of tumor spheroids of human breast cancer cell lines (MCF-7, ZR-75 and, SK-BR-3) in nude mice. Furthermore, we investigated if in the presence of effective VEGF blockade, a conventional chemotherapeutic drug (doxorubicin, (5 mg/kg, weekly) could be effective, and if so would there be an additive effect of the combination regimen. Tumor Spheroids were implanted in dorsal skinfold chambers in nude mice. Tumor cells were pre-labeled with a fluorescent vital dye (CMTMR), which allowed the estimation of growth of implanted tumor spheroids. FITC (fluorescein isothiocyanate)-Dextran was used to evaluate formation of neo-vasculature at the tumor site. In control animals all three cell-lines produced extensive neovasculature and there was significant tumor growth throughout the observation period. Treatment with the anti-VEGF mAb caused significant suppression of angiogenic activity for all cell lines, stressing the critical role VEGF plays in breast tumor angiogenesis. Doxorubicin alone reduced the growth rate of MCF-7 cells, but did not significantly affect angiogenesis. Doxorubicin in combination with A4.6.1 resulted in significant tumors regression. Histology indicated that some chambers lacked viable tumor cells at the end of the two week observation period, lending strong support that neutralization of VEGF in combination with conventional cytotoxic agents could be a new innovative treatment regimen for metastatic breast cancer.
TL;DR: Whether stealth liposomal doxorubicin accumulates selectively in bone metastases based on clinical material obtained from two patients with breast carcinoma is determined.
Abstract: BACKGROUND
Stealth liposomes hold promise as a mode of delivering cytotoxic agents selectively to tumors in cancer patients. The objective of this study was to determine whether stealth liposomal doxorubicin accumulates selectively in bone metastases based on clinical material obtained from two patients with breast carcinoma.
METHODS
Tumor tissue was obtained from two women (ages 33 years and 41 years, respectively) with metastatic breast carcinoma who responded to treatment with stealth liposomal doxorubicin and later underwent a surgical fixation procedure to treat a pathologic fracture of the femur. Drug levels in the tumor and adjacent muscle were examined by high performance liquid chromatography analysis in both patients and by fluorescence microscopy in one of the patients.
RESULTS
Bone tumor fragments obtained during surgery performed 6 days after the administration of the 12th course of stealth liposomal doxorubicin in 1 patient and 12 days after the administration of the 16th course of stealth liposomal doxorubicin in the second patient had a 10-fold greater concentration of liposomal doxorubicin than tumor free muscle. Doxorubicin fluorescence and specific nuclear staining showed good colocalization, thus confirming the presence of the liposome-delivered drug in the nuclei of tumor cells.
CONCLUSIONS
Using skeletal muscle as a comparator, stealth liposomal doxorubicin accumulates selectively in metastatic breast carcinoma cells within bone. Cancer 1999;86:72–8. © 1999 American Cancer Society.
TL;DR: Findings show that by inhibiting a (perhaps novel) drug‐activated acid sphingomyelinase and ceramide generation, L‐carnitine can prevent doxorubicin‐induced apoptosis of cardiac myocytes.
Abstract: Besides the well-documented effect of the chemotherapeutic drug doxorubicin on free radical generation, the exact signaling mechanisms by which it causes cardiac damage remain largely unknown and a...
TL;DR: LRP is involved in resistance to doxorubicin, vincristine, etoposide, paclitaxel, and gramicidin D and has an important role in the transport of doxorbicin from the nucleus to the cytoplasm.
Abstract: Background: Lung resistance-related protein (LRP), the major vault protein in humans, is sometimes overexpressed in multidrug-resistant cells. Because cells transfected with the LRP gene did not express the multidrug-resistant phenotype, we investigated whether LRP is involved in multidrug resistance. Methods: SW-620 cells, a human colon carcinoma cell line, alone or transfected with an expression vector carrying a LRP-specific ribozyme or with an empty vector, were treated with sodium butyrate to induce differentiation. Expression of P-glycoprotein, multidrug resistance protein, and LRP in the cells was examined by northern and western blotting, and the efflux of doxorubicin in the cells or isolated nuclei was examined by fluorescence microscopy. Results: A 2-week treatment with sodium butyrate induced LRP and conferred resistance to doxorubicin, vincristine, etoposide, gramicidin D, and paclitaxel (Taxol) in SW-620 cells. Insertion of either of two LRP-specific ribozymes into SW-620 cells inhibited these activities. Levels of drugs accumulating in the cells were not decreased by sodium butyrate, suggesting that the adenosine triphosphate-binding cassette transporter is not involved in sodium butyrate-induced multidrug resistance. Doxorubicin was mainly located in the nuclei of untreated cells and in the cytoplasm of sodium butyratetreated cells. Isolated nuclei from untreated cells or sodium butyrate-treated cells incubated with anti-LRP polyclonal antibodies contained more doxorubicin than the nuclei of sodium butyrate-treated cells alone. Efflux of doxorubicin was greater from the nuclei of sodium butyrate-treated cells than the nuclei of untreated cells or of sodium butyratetreated cells transfected with a LRP-specific ribozyme and was inhibited by an anti-LRP polyclonal antibody. Conclusions: LRP is involved in resistance to doxorubicin, vincristine, etoposide, paclitaxel, and gramicidin D and has an important role in the transport of doxorubicin from the nucleus to the cytoplasm. [J Natl Cancer Inst 1999;91:1647‐53]
Journal Article•
TL;DR: Results indicate that ROS are involved in the interaction between 1,25(OH)2D3 and doxorubicin, and suggest increased efficacy of 1, 25(OH), the hormonal form of vitamin D, or its analogues in combination with other ROS-generating anticancer therapeutic modalities.
Abstract: 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonal form of vitamin D, has anticancer activity in vivo and in vitro. Doxorubicin exerts its cytotoxic effect on tumor cells mainly by two mechanisms: (a) generation of reactive oxygen species (ROS); and (b) inhibition of topoisomerase II. We studied the combined cytotoxic action of 1,25(OH)2D3 and doxorubicin on MCF-7 breast cancer cells. Pretreatement with 1,25(OH)2D3 resulted in enhanced cytotoxicity of doxorubicin. The average enhancing effect after a 72-h pretreatment with 1,25(OH)2D3 (10 nM) followed by a 24-h treatment with 1 microg/ml doxorubicin was 74+/-9% (mean +/- SE). Under these experimental conditions, 1,25(OH)2D3 on its own did not affect cell number or viability. 1,25(OH)2D3 also enhanced the cytotoxic activity of another ROS generating quinone, menadione, but did not affect cytotoxicity induced by the topoisomerase inhibitor etoposide. The antioxidant N-acetylcysteine slightly reduced the cytotoxic activity of doxorubicin but had a marked protective effect against the combined action of 1,25(OH)2D3 and doxorubicin. These results indicate that ROS are involved in the interaction between 1,25(OH)2D3 and doxorubicin. 1,25(OH)2D3 also increased doxorubicin cytotoxicity in primary cultures of rat cardiomyocytes. Treatment of MCF-7 cells with 1,25(OH)2D3 alone markedly reduced the activity, protein, and mRNA levels of the cytoplasmic antioxidant enzyme Cu/Zn superoxide dismutase, which indicated that the hormone inhibits its biosynthesis. This reduction in the antioxidant capacity of the cells could account for the synergistic interaction between 1,25(OH)2D3 and doxorubicin and may also suggest increased efficacy of 1,25(OH)2D3 or its analogues in combination with other ROS-generating anticancer therapeutic modalities.
TL;DR: In this paper, an inducible expression of p21waf in the p53-null lung cancer cell line H1299, based on the muristerone-regulated system, was established.
Abstract: The CDK inhibitor p21waf is a principal mediator of p53 function but can also be transactivated by many p53-independent stimuli leading to cell growth arrest or differentiation. In order to study the function of p21waf in a p53-deficient environment, we established an inducible expression of p21waf in the p53-null lung cancer cell line H1299, based on the muristerone-regulated system. Overexpression of p21waf led cells to growth arrest which after several days became irreversible and the arrested cells acquired a senescent phenotype as judged by cell shape, the senescence-associated beta-gal marker and inhibition of colony formation. The effect of p21waf overexpression, in the absence of p53, on the cytotoxicity caused by irradiation, doxorubicin and taxol was studied. Expression of p21waf provided protection against the cytotoxic effect of radiation and doxorubicin but not of taxol. These results are relevant to treatment of cancer when p53 is inactive.
TL;DR: The combination of HSV-1716 with common chemotherapeutic agents may augment the effect of HSv-based therapy in the treatment of NSCLC.
Abstract: A replication-selective herpes simplex virus type 1 ICP34.5 mutant (HSV-1716) has shown efficacy both in vitro and in vivo against human non-small cell lung cancer (NSCLC) cell lines but complete eradication of tumor has not been accomplished with a single viral treatment in our murine xenograft models. Therefore, strategies to enhance the efficacy of this treatment were investigated. We determined the oncolytic activity of HSV-1716 in NCI-H460 cells in combination with each of four chemotherapeutic agents: mitomycin C (MMC), cis-platinum II (cis-DDP), methotrexate (MTX), or doxorubicin (ADR). Isobologram analysis was performed to evaluate the interaction between the viral and chemotherapeutic agents. The oncolytic effect of HSV-1716 in combination with MMC was synergistic in two of five NSCLC cell lines. In the other three cell lines, the combined effect appeared additive. No antagonism was observed. The in vivo effect of this combination was then examined in a murine xenograft model. NCI-H460 flank tumo...
Journal Article•
TL;DR: The results show the feasibility of in vivo P-gp function measurement under basal conditions and after modulation in solid tumors and in the brain, and PET and radiolabeled P-GP substrates may be useful as a clinical tool to select patients who might benefit from the addition of a P- gp modulator to MDR drugs.
Abstract: Drug resistance is a major cause of chemotherapy failure in cancer treatment. One reason is the overexpression of the drug efflux pump P-glycoprotein (P-gp), involved in multidrug resistance (MDR). In vivo pharmacokinetic analysis of P-gp transport might identify the capacity of modulation by P-gp substrate modulators, such as cyclosporin A. Therefore, P-gp function was measured in vivo with positron emission tomography (PET) and [11C]verapamil as radiolabeled P-gp substrate. Studies were performed in rats bearing tumors bilaterally, a P-gp-negative small cell lung carcinoma (GLC4) and its P-gp-overexpressing subline (GLC4/P-gp). For validation, in vitro and biodistribution studies with [11C]daunorubicin and [11C]verapamil were performed. [11C]Daunorubicin and [11C]verapamil accumulation were higher in GLC4 than in GLC4/P-gp cells. These levels were increased after modulation with cyclosporin A in GLC4/P-gp. Biodistribution studies showed 159% and 185% higher levels of [11C]daunorubicin and [11C]verapamil, respectively, in GLC4 than in GLC4/P-gp tumors. After cyclosporin A, [11C]daunorubicin and [11C]verapamil content in the GLC4/P-gp tumor was raised to the level of GLC4 tumors. PET measurements demonstrated a lower [11C]verapamil content in GLC4/P-gp tumors compared with GLC4 tumors. Pretreatment with cyclosporin A increased [11C]verapamil levels in GLC4/P-gp tumors (184%) and in brains (1280%). This pharmacokinetic effect was clearly visualized with PET. These results show the feasibility of in vivo P-gp function measurement under basal conditions and after modulation in solid tumors and in the brain. Therefore, PET and radiolabeled P-gp substrates may be useful as a clinical tool to select patients who might benefit from the addition of a P-gp modulator to MDR drugs.
TL;DR: The future holds increasing indications for taxanes in newer combination regimens; consideration of their pharmacologic characteristics is an important aspect of designing and applying new taxane-based treatment regimens.
TL;DR: In this paper, the authors investigated the effect of heat shock protein 27 (hsp27) overexpression on doxorubicin-induced apoptosis, finding that hsp27 protects MDA-MB-231 cells from apoptosis.
Abstract: Previously we demonstrated that heat shock protein 27 (hsp27) overexpression confers resistance to the chemotherapeutic agent doxorubicin in MDA-MB-231 breast cancer cells. Since induction of apoptosis is one underlying mechanism of chemotherapeutic drug action, we investigated the effect of hsp27 overexpression on doxorubicin-induced apoptosis, finding that hsp27 protects MDA-MB-231 cells from apoptosis. We also examined expression of the doxorubicin target, topoisomerase II (topo II), in control and hsp27-overexpressing stable transfectants, as topo II expression is important for both drug sensitivity and the initiation of apoptosis by doxorubicin. The relative levels of both topo IIalpha and beta were higher in the controls than the hsp27-overexpressing clones, suggesting that the apoptotic protective effect of hsp27 overexpression in MDA-MB-231 cells is associated with altered topo II expression.
Journal Article•
TL;DR: Positive results from clinical studies led to the approval of trastuzumab in the U.S in October 1998 for the treatment of metastatic breast cancer in patients with tumors overexpressing HER2, and the MAb has also been marketed in Switzerland and Canada.
Abstract: The HER2/neu gene encodes a 185 kDa transmembrane receptor (HER2) that belongs to the epidermal growth factor receptor family and has intrinsic tyrosine kinase activity. HER2 is overexpressed in 25-30% of breast cancers and is suggested to have a direct role in the pathogenesis and clinical aggressiveness of HER2 overexpressing tumors. A murine monoclonal antibody, 4D5, directed against the extracellular domain of HER2, is a potent inhibitor of growth of human breast cancer cells overexpressing HER2 in vitro and in xenograft models. To facilitate clinical investigation, 4D5 was humanized by inserting the complementary determining regions of 4D5 into the framework of a consensus human IgG1. The resulting recombinant humanized anti-HER2 MAb, trastuzumab, was found to inhibit the growth of human cancer cells and tumor xenografts overexpressing HER2. Data from phase II trials in women with breast cancer whose tumors overexpress HER2 have shown that trastuzumab has a favorable toxicity profile, is active as a single agent and induces long-lasting objective tumor responses. In combination studies, there was no evidence that trastuzumab enhanced the toxicity of cisplatin and the pharmacokinetic parameters of trastuzumab were unaltered by coadministration of cisplatin. Furthermore, clinical response rates were higher than those reported with either agent alone in a similar patient population. Results of a multicenter, phase III clinical trial of chemotherapy (doxorubicin- or paclitaxel-based) plus trastuzumab as compared to chemotherapy alone in patients with advanced breast cancers overexpressing HER2 showed a significant enhancement in the effects of chemotherapy on time to disease progression, response rates and survival with coadministration of trastuzumab, without increases in overall severe adverse events. Myocardial dysfunction syndrome, similar to that observed with anthracyclines, was reported more commonly with chemotherapy plus trastuzumab. Positive results from clinical studies led to the approval of trastuzumab in the U.S in October 1998 for the treatment of metastatic breast cancer in patients with tumors overexpressing HER2. Since then, the MAb has also been marketed in Switzerland and Canada.
TL;DR: Several immunoconjugates have demonstrated impressive antigen-specific antitumor activity in preclinical models and have the potential to both improve efficacy and reduce systemic toxicity in monoclonal-antibody-directed drug delivery.
Journal Article•
TL;DR: Results in two species demonstrate that the cardiotoxicity of doxorubicin is significantly decreased when administered as PL-DOX, and can be given without incurring an increased risk of cardiomyopathy.
Abstract: The relative cardiotoxicity of pegylated (STEALTH) liposomal doxorubicin (PL-DOX; Doxil) was compared to nonliposomal doxorubicin (Adriamycin) in rabbits and dogs treated i.v. for up to 22 weeks. No histological evidence of cardiotoxicity was seen in dogs treated with placebo liposomes or PL-DOX every 3 weeks for a total of 10 doses (cumulative doxorubicin dose = 10 mg/kg) either 1 or 5 weeks post-treatment. All dogs treated with the same cumulative dose of free doxorubicin showed marked cardiotoxicity (vacuolization and myofibrillar loss in the myocardium) at both time points. In rabbits, progressive cardiomyopathy was seen in both treatment groups, but was more frequent and severe with free doxorubicin (67% of doxorubicin-treated rabbits, cumulative dose = 12 to 14 mg/kg versus 16% of PL-DOX-treated animals, cumulative dose = 14 to 21 mg/kg). Five doxorubicin-treated rabbits died of congestive heart failure or with histologic evidence of cardiotoxicity (median severity score = 6). No PL-DOX-treated rabbits died of congestive heart failure, although two animals that died early showed microscopic evidence of mild cardiotoxicity (median severity score = 2.5). Cardiotoxicity increased during the post-treatment period in both treatment groups. Rabbits received up to 50% more PL-DOX with no increase in cardiotoxicity. Thus, results in two species demonstrate that the cardiotoxicity of doxorubicin is significantly decreased when administered as PL-DOX. Significantly more PL-DOX can be given without incurring an increased risk of cardiomyopathy. Recent clinical studies have confirmed that PL-DOX is also less cardiotoxic than the same dose of unencapsulated doxorubicin in humans.
TL;DR: Univariate analysis showed that, in stage‐III and ‐IV patients, younger age, no residual tumour after first laparotomy, response to first‐line chemotherapy and absence of hsp27 expression were associated with longer median progression‐free survival, however, in multivariate analysis, only age, ascites and response to chemotherapy retained independent prognostic value.
Abstract: Heat-shock protein 27 (hsp27) is one of the small heat-shock proteins. Its expression in ovarian- and breast-cancer cell lines has been associated with resistance to cisplatin and doxorubicin. In addition, hsp27 expression appears to facilitate cellular growth, differentiation and motility. In several human carcinomas, hsp27 expression might also be related to worse prognosis. The aim of this study was to evaluate the prognostic value of hsp27 expression in patients with ovarian carcinoma in relation to their response to chemotherapy and overall survival. Hsp27 expression was assessed by immunohistochemistry in 77 patients with ovarian carcinoma stage IC-IV. All patients received cisplatin- and doxorubicin-based chemotherapy and had long-term follow-up. In 30 patients, paired tumour samples were available, obtained before and after chemotherapy. Hsp27 immunostaining was positive in 86% of patients before and in 72% of patients after chemotherapy. Hsp27 expression was not related to any clinicopathologic factor, including previously determined p53 expression. Univariate analysis showed that, in stage-III and -IV patients, younger age, no residual tumour after first laparotomy, < or = 1 litre ascites, response to first-line chemotherapy and absence of hsp27 expression were associated with longer median progression-free survival. However, in multivariate analysis, only age, ascites and response to chemotherapy retained independent prognostic value.
TL;DR: Results regarding the effect of an acid-sensitive PEG conjugate of molecular weight 20000 in the chorioallantoic membrane (CAM) assay indicate that this conjugates is significantly less embryotoxic than free doxorubicin although antiangiogenic effects were not observed.
TL;DR: There was enhanced efficacy using the three drug combination of p53 Ad, cisplatin, and paclitaxel in an ovarian cancer model and these results support the combination of the p53 gene therapy with chemotherapy in clinical trials.
Abstract: Purpose: Adenovirus-mediated p53 gene therapy for cancer is currently undergoing phase I/II clinical trials. The drug used in our clinical trials (p53 Ad; ACN53; SCH58500) consists of a replication-deficient, type 5 adenovirus vector expressing human wildtype p53 tumor suppressor under the control of the cytomegalovirus promoter. In preclinical models, p53 Ad has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53, both in vitro and in vivo. Results from early clinical trials using p53 gene therapy by itself support optimism for the future of this therapeutic approach. However, it is likely that many phase II/III trials will incorporate an arm comparing traditional chemotherapy against chemotherapy combined with p53 gene therapy. Therefore, it is important to study possible interactions between p53 Ad and chemotherapeutic drugs in preclinical models before starting the clinical trials. Methods: Proliferation of tumor cells was quantitated after incubation with various combinations of p53 Ad and chemotherapeutic drugs. Human tumor xenografts in scid mice were dosed with intraperitoneal or intratumoral p53 Ad with or without chemotherapeutic drugs and the tumor burden after therapy monitored. Results: p53 Ad combined with cisplatin, doxorubicin, 5-fluorouracil, methotrexate, or etoposide inhibited cell proliferation more effectively than chemotherapy alone in SCC-9 head and neck, SCC-15 head and neck, SCC-25 head and neck, SK-OV-3 ovarian, DU-145 prostate, MDA-MB-468 breast, and MDA-MB-231 breast tumor cells. No obvious dependence on dosing schedule was observed. Greater anticancer efficacy was also demonstrated in four human tumor xenograft models in vivo. Of particular significance, there was enhanced efficacy using the three drug combination of p53 Ad, cisplatin, and paclitaxel in an ovarian cancer model. Conclusion: These results support the combination of p53 gene therapy with chemotherapy in clinical trials.
TL;DR: Topical 99% dimethylsulfoxide (DMSO) also has shown strong activity in treating tissue extravasation reactions during intravenous administration of doxorubicin.
Abstract: Purpose: Chemotherapeutic regimens that utilize fluorouracil, cytarabine, and doxorubicin have been shown to cause a dermatologic syndrome known as hand-foot syndrome, or palmar-plantar erythrodysesthesia syndrome (PPES). Pegylated liposomal doxorubicin has proven effective in the treatment of AIDS-related Kaposi's sarcoma, ovarian cancer refractory to platinum and paclitaxel therapies, and metastatic breast cancer. In a study of the treatment of refractory epithelial cell ovarian cancers with lipozomal doxorubicin utilizing intravenous doses of 50 mg/m2 every 3 weeks, grade 3 PPES was observed in 29% of patients (10/35) and required dose reductions and/or dose delay after a median of three therapy cycles. Methods: Current methods to prevent pegylated liposomal doxorubicin-induced PPES include dose reduction, lengthening of the drug administration interval and ultimately, drug withdrawal. Topical 99% dimethylsulfoxide (DMSO) also has shown strong activity in treating tissue extravasation reactions during intravenous administration of doxorubicin. Results: Two patients undergoing chemotherapy with pegylated liposomal doxorubicin, 50 mg/m2 every 4 weeks, developed grade 3 PPE after three cycles. Their PPES resolved over a period of 1 to 3 weeks while receiving topical 99% DMSO four times daily for 14 days. Conclusions: While these results are promising, patients must be treated in a prospective study of this topical DMSO formulation to definitively document its therapeutic efficacy.