Showing papers on "Doxorubicin published in 1997"
TL;DR: A modification of the general anthracycline ring structure results in analogues with different but overlapping antitumour and tolerability profiles as discussed by the authors, which can be used to improve the anti-malignancy properties of the drugs.
Abstract: Anthracyclines are widely used and effective antineoplastic drugs. Although active against a wide variety of solid tumours and haematological malignancies, their clinical use is hindered by tumour resistance and toxicity to healthy tissue. Modification of the general anthracycline ring structure results in analogues with different but overlapping antitumour and tolerability profiles. Activity of the anthracyclines is related to topoisomerase II inhibition, which occurs as a result of anthracycline intercalation between adjacent DNA base pairs. Production of hydroxyl free radicals is associated with antitumour effects and toxicity to healthy tissues. Myocardial tissue is particularly susceptible to free radical damage. Development of tumour cell resistance to anthracyclines involves a number of mechanisms, including P-glycoprotein-mediated resistance. The classical dose-limiting adverse effects of this class of drugs are acute myelosuppression and cumulative dose-related cardiotoxicity. Anthracycline-induced cardiomyopathy is often irreversible and may lead to clinical congestive heart failure. Other toxicities of the anthracyclines, including stomatitis, nausea and vomiting, alopecia and 'radiation recall' reactions, are generally reversible. Anthracycline-induced cardiotoxicity may be reduced or prevented by an administration schedule that produces low peak plasma drug concentrations. Administration of dexrazoxane also provides cardioprotection. Dose intensification of anthracyclines may partly overcome resistance but is associated with reduced tolerability. Liposomal encapsulation of doxorubicin or daunorubicin alters the pharmacokinetic properties of the drugs. Increased distribution in tumours, prolonged circulation and reduced free drug concentrations in plasma may increase antitumour activity and improve the tolerability of the anthracyclines.
649 citations
TL;DR: Liposomal doxorubicin has substantial activity against ovarian cancer refractory to platinum and paclitaxel and this liposomal formulation should be evaluated further in combination with other drugs in lessRefractory patients.
Abstract: PURPOSEA phase II study of liposomal doxorubicin was conducted in patients with ovarian cancer who failed to respond to platinum- and paclitaxel-based regimens. Liposomal doxorubicin was selected as a result of its superior activity against ovarian cancer xenografts relative to free doxorubicin and activity in refractory ovarian cancer patients that was noted during the phase I study.PATIENTS AND METHODSThirty-five consecutive patients were accrued in two institutions (22 in one and 13 in the other). All had progressive disease after either cisplatin or carboplatin and paclitaxel, or at least one platinum-based and one paclitaxel-based regimen. Patients received intravenous (I.V.) liposomal doxorubicin 50 mg/m2 every 3 weeks with a dose reduction to 40 mg/m2 in the event of grade 3 or 4 toxicities, or a lengthening of the interval to 4 weeks (and occasionally to 5 weeks) with persistence of grade 1 or 2 toxicities beyond 3 weeks.RESULTSNine clinical responses (one complete response [CR], eight partial res...
643 citations
Journal Article•
TL;DR: In this paper, the human epidermal growth factor receptor blocks activation of receptor tyrosine kinase, which retards or arrests cell cycle progression, with accumulation of cells in G1 phase.
Abstract: Monoclonal antibody (mAb) 225 against the human epidermal growth factor receptor blocks activation of receptor tyrosine kinase. This retards or arrests cell cycle progression, with accumulation of cells in G1 phase. The mechanism of growth inhibition involves increased levels of p27KIP1 and inhibition of cyclin-dependent kinase-2 activity. mAb in combination with chemotherapy exhibits a synergistic antitumor activity, with successful eradication of well-established tumor xenografts that resist treatment with either mAb or drug alone. A Phase I clinical trial has established the safety of repeated administration of human:mouse chimeric mAb 225 at concentrations that maintain receptor-saturating blood levels for up to 3 months. Phase I trials exploring mAb 225 treatment in combination with doxorubicin, cisplatin, or paclitaxel are ongoing.
372 citations
TL;DR: It is shown that unfertilized mouse oocytes exposed to therapeutic levels of the antitumor drug, doxorubicin (DXR), undergo apoptosis; however, fertilized oocytes do not initiate apoptosis, but enter cell-cycle arrest, when treated with DXR.
Abstract: Female sterility resulting from oocyte destruction is an unfortunate, and in many cases inevitable, consequence of chemotherapy. We show that unfertilized mouse oocytes exposed to therapeutic levels of the antitumor drug, doxorubicin (DXR), undergo apoptosis; however, fertilized oocytes do not initiate apoptosis, but enter cell-cycle arrest, when treated with DXR. Apoptosis induced by DXR in oocytes is blocked by sphingosine-1-phosphate, an inhibitor of ceramide-promoted cell death. Oocytes from Bax-deficient, but not p53-null, female mice display complete resistance to DXR-induced apoptosis in vivo and in vitro. Pretreatment of oocytes with a specific peptide inhibitor of caspases also abrogates the apoptotic response to DXR. These findings indicate that oocyte destruction caused by chemotherapy can be prevented by manipulation of apoptosis-associated signaling pathways.
370 citations
TL;DR: It is shown that the antioxidants pyrrolidinedithiocarbamate and vitamin E induce apoptosis in CRC Cells, and chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.
Abstract: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Five-fluorouracil (5FU) remains the single most effective treatment for advanced disease, despite a response rate of only 20%. Herein, we show that the antioxidants pyrrolidinedithiocarbamate and vitamin E induce apoptosis in CRC cells. This effect is mediated by induction of p21WAF1/CIP1, a powerful inhibitor of the cell cycle, through a mechanism involving C/EBPbeta (a member of the CCAAT/enhancer binding protein family of transcription factors), independent of p53. Antioxidants significantly enhance CRC tumor growth inhibition by cytotoxic chemotherapy in vitro (5FU and doxorubicin) and in vivo (5FU). Thus, chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.
353 citations
TL;DR: Findings suggest that MDR modulation may delay the emergence of clinical drug resistance and support the concept of prevention of drug resistance in the earlier stages of disease.
Abstract: Intrinsic and acquired multidrug resistance (MDR) in many human cancers may be due to expression of the multidrug transporter P-glycoprotein (Pgp), which is encoded by the mdr1 gene. There is substantial evidence that Pgp is expressed both as an acquired mechanism (e.g., in leukemias, lymphomas, myeloma, and breast and ovarian carcinomas) and constitutively (e.g., in colorectal and renal cancers) and that its expression is of prognostic significance in many types of cancer. Clinical trials of MDR modulation are complicated by the presence of multiple-drug-resistance mechanisms in human cancers, the pharmacokinetic interactions that result from the inhibition of Pgp in normal tissues, and, until recently, the lack of potent and specific inhibitors of Pgp. A large number of clinical trials of reversal of MDR have been undertaken with drugs that are relatively weak inhibitors and produce limiting toxicities at doses below those necessary to inhibit Pgp significantly. The advent of newer drugs such as the cyclosporin PSC 833 (PSC) provides clinicians with more potent and specific inhibitors for MDR modulation trials. Understanding how modulators of Pgp such as PSC 833 affect the toxicity and pharmacokinetics of cytotoxic agents is fundamental for the design of therapeutic trials of MDR modulation. Our studies of combinations of high-dose cyclosporin (CsA) or PSC 833 with etoposide, doxorubicin, or paclitaxel have produced data regarding the role of Pgp in the clinical pharmacology of these agents. Major pharmacokinetic interactions result from the coadministration of CsA or PSC 833 with MDR-related anticancer agents (e.g., doxorubicin, daunorubicin, etoposide, paclitaxel, and vinblastine). These include increases in the plasma area under the curve and half-life and decreases in the clearance of these cytotoxic drugs, consistent with Pgp modulation at the biliary lumen and renal tubule, blocking excretion of drugs into the bile and urine. The biological and medical implications of our studies include the following. First, Pgp is a major organic cation transporter in tissues responsible for the excretion of xenobiotics (both drugs and toxins) by the biliary tract and proximal tubule of the kidney. Our clinical data are supported by recent studies in mdr-gene-knockout mice. Second, modulation of Pgp in tumors is likely to be accompanied by altered Pgp function in normal tissues, with pharmacokinetic interactions manifesting as inhibition of the disposition of MDR-related cytotoxins (which are transport substrates for Pgp). Third, these pharmacokinetic interactions of Pgp modulation are predictable if one defines the pharmacology of the modulating agent and the combination. The interactions lead to increased toxicities such as myelosuppression unless doses are modified to compensate for the altered disposition of MDR-related cytotoxins. Fourth, in serial studies where patients are their own controls and clinical resistance is established, remissions are observed when CsA or PSC 833 is added to therapy, even when doses of the cytotoxin are reduced by as much as 3-fold. This reversal of clinical drug resistance occurs particularly when the tumor cells express the mdr1 gene. Thus, tumor regression can be obtained without apparent increases in normal tissue toxicities. In parallel with these trials, we have recently demonstrated in the laboratory that PSC 833 decreases the mutation rate for resistance to doxorubicin and suppresses activation of mdr1 and the appearance of MDR mutants. These findings suggest that MDR modulation may delay the emergence of clinical drug resistance and support the concept of prevention of drug resistance in the earlier stages of disease and the utilization of time to progression as an important endpoint in clinical trials. Pivotal phase III trials to test these concepts with PSC 833 as an MDR modulator are under way or planned for patients with acute myeloid leukemias, multiple myeloma, and ovarian carcinoma.
296 citations
TL;DR: It is unlikely that activation of NF-kappaB caused by antineoplastic agents or by paclitaxel is mediated via cytokine up-regulation, as two other groups of anticancer drugs including vinca alkaloids and anthracyclines, neither of which induce TNF or interleukin-1 gene expression, were examined.
275 citations
TL;DR: PTX, as clinically formulated in CEL, is responsible for a nonlinear disposition of DOX and DOL, and possibly caused by competition for biliary excretion of taxanes and anthracyclines mediated by P-gp.
Abstract: PURPOSEWe performed a pharmacologic investigation of paclitaxel (PTX) infused over 3 hours and bolus doxorubicin (DOX) to assess the role of sequence, interval between drugs, and duration of doxorubicin infusion on paclitaxel and anthracycline plasma disposition. We also explored possible mechanisms of pharmacokinetic interference involving the physiologic role of the multidrug resistance phenotype in anthracycline and taxane biliary excretion.PATIENTS AND METHODSPharmacokinetics was performed in 80 cycles and 36 women with previously untreated metastatic breast cancer. PTX, DOX, and their metabolites 6 alpha-hydroxyl-PTX (6 alpha OH-PTX) and doxorubicinol (DOL) were measured by high-pressure liquid chromatography (HPLC). Human breast cancer MCF-7 wild-type (WT) and resistant (TH) cell lines were cultured in whole human plasma to study anthracycline retention after treatment with different combinations of PTX, Cremophor EL (CEL) (PEG35 castor oil; BASF, Parsippany, NJ), and DOX.RESULTSPharmacokinetic inte...
262 citations
TL;DR: In vivo and in vitro, synergistic antiproliferative effects were observed when oxaliplatin was added to 5-FU and AG337, and synergistic effects of combinations were maintained in colon HT29-5-FU cancer cells.
Abstract: Oxaliplatin, classical [5-fluorouracil (5-FU)] and non-classical (AG337) thymidylate synthase inhibitors have shown promising activity in the treatment of cancer. This study investigates the cytotoxic effects of oxaliplatin in combination with 5-FU and AG337 in cultured human colon (HT29, CaCo2), breast (MCF-7, MDA-MB-231) and ovarian (2008) cancer cell lines, and their derived counterparts selected for their resistance to 5-FU (HT29-5-FU), doxorubicin (MCF-7mdr) or cisplatin (2008C13). Therapeutic experiments were conducted in mice bearing colon-HT29 xenografts and in the GR hormone-independent mammary carcinoma model. In vitro, oxaliplatin shows potent cytotoxic activity in colon (IC50 from 2.1 +/- 1.1 to 5.9 +/- 1.7 microM), ovarian (IC50 = 10 +/- 1.6 microM) and breast cancer cells (IC50 from 7.4 +/- 2.7 to 17.9 +/- 7.1 microM). Oxaliplatin was a potent inhibitor of DNA synthesis and bound to cellular DNA. Surprisingly, the overall amount of oxaliplatin DNA binding was significantly inferior to that induced by isocytotoxic concentrations of cisplatin in HT29 (p=0.026). In vitro, synergistic antiproliferative effects were observed when oxaliplatin was added to 5-FU and AG337. Those synergistic effects of combinations were maintained in colon HT29-5-FU cancer cells. In vivo, 5-FU increased significantly the antitumor activity of oxaliplatin in HT29 xenografts (p=0.0036), and similarly 5-FU and AG337 increased the activity of oxaliplatin in the GR tumor model (p=0.0012). These data may encourage further clinical investigation of oxaliplatin in combination with classical and non-classical thymidylate synthase inhibitors in the treatment of human cancers.
237 citations
TL;DR: Liposome localization in tumors appears to be the result of an enhanced rate of extravasation through the abnormally permeable microvasculature of tumors coupled with an impaired lymphatic drainage.
224 citations
TL;DR: Chemotherapy provokes many significant changes in body composition and metabolic requirements, and additional research in this area will provide valuable insight into creating optimal interventions to curb weight gain in women with breast cancer.
TL;DR: Preliminary data, not yet confirmed in comparative studies, suggest that the pegylated liposomal formulation may be less cardiotoxic than free doxorubicin, and mucositis, however, appears to be increased.
Abstract: Encapsulation in polyethylene glycol-coated (pegylated; Stealth®) liposomes alters the pharmacokinetic characteristics, and hence the safety and tolerability profile, of doxorubicin. Pegylated liposomal doxorubicin administered as a single agent is generally well tolerated. Grade III/IV leucopenia, stomatitis and palmar-plantar erythrodysaesthesia affected 16, 6 and 18% of solid tumour patients, respectively. Other adverse effects included nausea and vomiting and alopecia. Acute hypersensitivity infusion reactions have been reported in up to 9% of patients in some studies. Recently published data from a phase II trial in patients with refractory ovarian cancer showed no alopecia or cardiotoxicity and little nausea and vomiting after pegylated liposomal doxorubicin. Unlike free doxorubicin, pegylated liposomal doxorubicin is not a vesicant. Preliminary data, not yet confirmed in comparative studies, suggest that the pegylated liposomal formulation may be less cardiotoxic than free doxorubicin. Mucositis, however, appears to be increased. Studies to determine optimal dosing schedules and safety of pegylated liposomal doxorubicin in combination with other agents are ongoing.
TL;DR: Of 28 patients who experienced disease progression while receiving combination regimens that contained standard doxorubicin, the PR rate was 32%, which suggests that the pegylated-liposomal encapsulation increases the therapeutic effect of doxorbicin.
Abstract: PURPOSETo determine the efficacy and safety of pegylated-liposomal doxorubicin in patients with AIDS and Kaposi's sarcoma (AIDS-KS) who experienced failure of standard chemotherapy.METHODSFifty-three patients with advanced AIDS-KS who experienced disease progression or intolerable toxicities while receiving standard doxorubicin/bleomycin/vincristine (ABV) or bleomycin/vincristine (BV) chemotherapy were identified from a cohort of patients who were then treated with pegylated-liposomal doxorubicin. Patients received 20 mg/m2 pegylated-liposomal doxorubicin (Doxil; Sequus Pharmaceuticals, Inc, Menlo Park, CA) every 3 weeks.RESULTSNineteen patients (36%) had a partial response (PR) and one patient had a clinical complete response (CCR). The median duration of response and time (from study entry) to treatment failure were 128 and 134 days, respectively. Of 28 patients who experienced disease progression while receiving combination regimens that contained standard doxorubicin, the PR rate was 32%, which sugges...
TL;DR: The results suggest that at pharmacologically relevant concentrations apoptosis and not oxidative DNA damage is the main killing mechanism of doxorubicin against ALL-cells.
TL;DR: Tissue concentrations of doxorubicin in small bowel, omentum, and spleen were significantly increased when the drug was administered by hyperthermic i.p. doxorbicin, while plasma aglycone concentrations in plasma, liver, and bladder increased significantly.
Abstract: Background: The cytotoxic effect of several anticancer agents, including doxorubicin, can be enhanced by hyperthermia. The purpose of this study was to evaluate the effect of hyperthermia on the pharmacokinetics, metabolism, and tissue distribution of intraperitoneal (i.p.) doxorubicin in a rodent model. Methods: Doxorubicin was given i.p. to 20 Sprague-Dawley rats at a dose of 2 mg/kg over 60 min. Rats were randomized into two groups according to the temperature of the peritoneal perfusate: group NT received normothermic (37 °C) i.p. doxorubicin; group HT received hyperthermic (43 °C) i.p. doxorubicin. During the course of i.p. chemotherapy, peritoneal fluid and blood were sampled every 10 min. At the end of the procedure, rats were sacrificed and tissue samples (liver, spleen, small bowel, omentum, bladder, diaphragm, abdominal wall, heart) were collected. Concentrations of doxorubicin and its aglycone metabolites were determined in peritoneal fluid, plasma, and tissues by HPLC. Results: No significant differences in areas under the curve (AUC) of peritoneal fluid doxorubicin and plasma doxorubicin were found between group NT and group HT. AUC ratios (AUC peritoneal fluid/AUC blood) were 87.9 for group NT and 82.9 for group HT. Group HT exhibited increased doxorubicin concentrations for all intraabdominal tissues. These differences were significant for spleen (P = 0.03), small bowel (P = 0.03), and omentum (P = 0.03). Doxorubicin aglycone was detected in plasma of both groups within the first 10 min of the procedure. There was a significant (P < 0.001) increase in plasma aglycone AUC for group HT when compared with group NT. Group HT exhibited increased aglycone concentration for all tissues. This difference was significant for liver (P < 0.001) and bladder (P < 0.001). Conclusion: Hyperthermia did not affect significantly the pharmacokinetics of i.p. doxorubicin. Tissue concentrations of doxorubicin in small bowel, omentum, and spleen were significantly increased when the drug was administered by hyperthermic i.p. perfusion. Hyperthermia increased significantly the doxorubicin aglycone concentrations in plasma, liver, and bladder.
TL;DR: Fluorescence microscopy showed that chloroquine affects vesicular anthracycline sequestration in U-A10 cells with an associated increase in daunorubicin nuclear fluorescence, and studies with the lysosomotropic agent chlorquine showed that U- A10 cells accumulated twofold more chloroquines and showed twofold enhanced sensitivity to this agent as compared with parental U-937 cells.
Journal Article•
TL;DR: Some of the benefits associated with the use of PEG-modified liposomes, such as increased blood levels and enhanced circulation lifetime, may be of little advantage in terms of maximizing liposomal drug accumulation in sites of tumor growth.
Abstract: The efficiency of drug accumulation in tumors was measured after intravenous administration of doxorubicin encapsulated in distearoyl phosphatidylcholine/cholesterol liposomes prepared in the presence or absence of 5 mol % polyethylene glycol-modified phosphatidylethanolamine (PEG-PE). These liposomal formulations of doxorubicin were administered at the maximum tolerated dose in female BDF-1 mice bearing subcutaneously established Lewis Lung carcinoma. The parameters used to determine tumor targeting efficiency (T(e)) included area under the doxorubicin plasma (AUC(P)) and tumor (AUC(T)) concentration-time curves. Extended time-course studies evaluating lipid and drug levels in plasma and tumors during 7 days after administration indicated that the T(e) (AUC(T)/AUC(P)) was greater for liposomes that did not contain PEG-PE. The AUC(P) after administration of free doxorubicin, doxorubicin encapsulated in distearoyl phosphatidylcholine/cholesterol liposomes and doxorubicin encapsulated in distearoyl phosphatidylcholine/cholesterol/PEG-PE-stabilized liposomes were 0.087 micromol x ml(-1) x h, 50 micromol x ml(-1) x h and 78 micromol x ml(-1) x h, respectively. Maximum drug levels achieved in the tumors were similar for both liposomal doxorubicin formulations, 140 microg (250 nmol)/g tumor; however, this level was achieved faster when the liposomes did not contain PEG-PE. Maximum levels measured after administration of free drug were less than 5 microg/g tumor, and these were achieved within 15 min. The results suggest that some of the benefits associated with the use of PEG-modified liposomes, such as increased blood levels and enhanced circulation lifetime, may be of little advantage in terms of maximizing liposomal drug accumulation in sites of tumor growth.
TL;DR: Immunoliposomes may prove useful as a tumor-targeted delivery system for a variety of anticancer agents, such as doxorubicin, by increasing tumor exposure and reducing toxicity to normal cells and tissues.
Abstract: Publisher Summary Immunoliposomes represent a rational strategy to achieve targeted drug delivery for cancer treatment. This chapter summarizes the recent developments in the use of immunoliposomes for cancer treatment. Because of their improved pharmacologic properties, sterically stabilized liposomes have generated renewed interest in liposomes as drug carriers. Sterically stabilized liposomes containing doxorubicin have shown encouraging clinical activity. Immunoliposomes (ILs) represent a further strategy to enhance liposomal drug delivery, by linking liposomes to monoclonal antibodies (MAbs) directed against tumor-associated antigens. Sterically stabilized immunoliposomes directed against tumor-associated antigens have been used to target murine squamous cell lung cancer cells in vitro and in vivo and murine fibrosarcoma cells in vitro . Immunoliposomes designed for intraperitoneal therapy have been used to target human ovarian cancer cells in vitro and in ascites fluid in vivo . In addition to targeting tumor-associated an igens, immunoliposomes have been developed to target endothelial cells. Anti-HER2 immunoliposome-mediated delivery of doxorubicin may represent a particularly advantageous strategy for the treatment of breast and other cancers with frequent HER2 overexpression. Moreover, anti-HER2 immunoliposome delivery of doxorubicin provides a means of limiting the toxicity of doxorubicin in normal tissues. Immunoliposomes may prove useful as a tumor-targeted delivery system for a variety of anticancer agents, such as doxorubicin, by increasing tumor exposure and reducing toxicity to normal cells and tissues. In addition to targeted delivery of small molecule drugs, improvements in immunoliposome design and construction may lead to new therapeutic applications, such as gene therapy.
TL;DR: It is concluded that measurement of topo II-alpha in invasive breast cancer can be readily performed by immunohistochemical staining, and it gives information on the number of cycling tumor cells.
TL;DR: None of the known proteins related to multidrug resistance predicted response to chemotherapy in breast cancer, and resistant clones left behind generally had a low proliferation rate.
Abstract: Drug resistance plays an important role in chemotherapy failure in breast cancer. We studied the expression of MDR1, MRP, LRP, DNA topoisomerases, p53 and Ki-67 in different groups of breast cancer patients in relation to chemotherapy. Tissues from 6 normal breasts and 20 primary operable, 40 locally advanced and 10 anthracycline-resistant metastatic breast cancers were assessed. Sequential samples of the same patient were available from 17 patients with locally advanced breast cancer undergoing neo-adjuvant chemotherapy and in 7 metastatic patients undergoing paclitaxel treatment. Protein expression was investigated by immunohistochemistry. Significantly higher protein expression was observed for Pgp, Ki-67 and p53 in the locally advanced breast cancers than in primary operable breast cancers. No other significant differences in protein expression were found among the 3 breast cancer groups. Expression of none of the markers that could be assessed (Pgp, MRP, LRP, p53 and Ki-67) in locally advanced breast cancer had predictive value for pathological response. Interestingly, after chemotherapy a significant decrease in percentage of Ki-67 positive tumor cells was observed, whereas the other markers did not vary substantially. Furthermore, considering all breast cancer samples, a cumulative dose of doxorubicin >400 mg/m2 inversely correlated with Ki-67 positivity. However, 2 patients with a pathological complete remission had only 5-10% Ki67-positive tumor cells before chemotherapy, indicating that Ki67 negativity itself is not responsible for chemoresistance. In conclusion, none of the known proteins related to multidrug resistance predicted response to chemotherapy in breast cancer, and resistant clones left behind generally had a low proliferation rate.
TL;DR: Overall, liposomal doxorubicin appears to be one of the most active single agents available for treating patients with AIDS-related Kaposi’s sarcoma, which is more effective than the best available combination chemotherapy regimens.
Abstract: Doxorubicin is an antineoplastic drug which has in vitro and in vivo activity against a number of malignancies including Kaposi’s sarcoma. Incorporation of doxorubicin into polyethylene glycol— coated (pegylated) liposomes alters the pharmacokinetics of the drug. Liposomal doxorubicin has a smaller volume of distribution and slower plasma clearance than standard free doxorubicin. The liposomal formulation achieves higher concentrations in the highly vascularised lesions of Kaposi’s sarcoma than in normal tissue. Liposomal doxorubicin monotherapy in patients with AIDS-related Kaposi’s sarcoma produced overall response rates (complete plus partial) of 43 and 59% in large comparative studies and 67 to 100% in noncomparative studies which included ≥ 20 patients. In comparative studies, liposomal doxorubicin was significantly more effective than the combination of standard doxorubicin, bleomycin and vincristine (overall response rates of 43 and 25%, respectively) and bleomycin and vincristine (BV) [overall response rates of 59 and 23%, respectively]. In addition, overall response rates to the liposomal drug were higher in both treatment arms of 2 smaller comparative studies which compared liposomal doxorubicin with BV, but significant between-treatment differences were not detected. Patient numbers in these 2 studies, however, may have been too small to detect significant differences. Liposomal doxorubicin is generally well tolerated. Myelosuppression is the most common dose-limiting adverse effect in patients with AIDS and Kaposi’s sarcoma. Neutropenia occurs most often; anaemia and thrombocytopenia occur less frequently, as do nausea and vomiting and stomatitis. Palmar-plantar erythrodysaesthesia occurs in some patients, most commonly after 6 to 8 weeks of chemotherapy. Although symptoms may occasionally be severe, the syndrome usually does not require dosage reduction or treatment delay. Limited data suggest that the incidence of cardiotoxicity may be lower after liposomal doxorubicin than after equivalent doses of standard doxorubicin. Overall, liposomal doxorubicin appears to be one of the most active single agents available for treating patients with AIDS-related Kaposi’s sarcoma. The therapeutic potential of liposomal doxorubicin administered in combination with other active agents to patients with Kaposi’s sarcoma is, as yet, unknown. However, administered alone, the drug seems to be more effective than the best available combination chemotherapy regimens. Doxorubicin is an anthracycline cytostatic antibiotic with activity against a variety of malignancies including Kaposi’s sarcoma. In vitro and in vivo, polyethylene glycol-coated (pegylated) liposomal doxorubicin inhibits the growth of Kaposi’s sarcoma cells. Kaposi’s sarcoma spindle cell cultures were more sensitive to liposomal doxorubicin than cultures of normal monocytes, or normal endothelial or smooth muscle cells. Tumour cell DNA fragmentation induced by doxorubicin is a result of topoisomerase II inhibition which occurs when the drug intercalates between DNA strands. Antitumour activity and drug toxicity may also relate to the formation of intracellular oxygen free radicals, which are produced by reduction of the doxorubicin molecule. In addition, liposomal doxorubicin induces expression of monocyte chemoattractant protein-1, which results in intralesional recruitment of phagocytic cells in patients with Kaposi’s sarcoma. The pharmacokinetic profile of liposomal doxorubicin is substantially different from that of standard free doxorubicin. Compared with standard doxorubicin, the liposomal product distributes in a smaller volume (254 vs 4.1L), has a larger area under the plasma concentration-time curve and is cleared from the body more slowly (total plasma clearance 45.3 vs 0.08 L/h). In biopsy specimens obtained 48 and 96 hours after administration of liposomal doxorubicin to patients with AIDS-related Kaposi’s sarcoma, higher drug concentrations were present in Kaposi’s sarcoma lesions than in normal skin tissue. The distribution half-life of liposomal doxorubicin is approximately 45 to 56 hours. Metabolites, including doxorubicinol, were detected in the urine, but not the plasma, of liposomal doxorubicin-treated patients, indicating that the metabolism of liposomal doxorubicin is similar to that of the free drug but that the rate of metabolite excretion is higher than the rate of metabolism. The effect of hepatic dysfunction on the clearance of liposomal doxorubicin is unclear; however, volume of distribution, clearance and elimination half-life in patients with mild to moderate hepatic dysfunction did not appear to be altered compared with values from historical controls. Clinical studies of liposomal doxorubicin in Kaposi’s sarcoma predominantly included men with AIDS, CD4+ counts <200 cells/μl and good performance status. Most patients were classified according to AIDS Clinical Trials Group (ACTG) criteria as ‘poor risk’. Liposomal doxorubicin is a highly active single agent in these patients. Overall response rates (complete plus partial) of 43 and 59% have been reported in large comparative trials. In noncomparative studies which included ≥20 patients and predominantly assessed liposomal doxorubicin 20 mg/m2 administered at 2- or 3-week intervals, overall response rates of 67 to 100% were reported. In the largest noncomparative study (n=238; overall response rate 81 %), no correlation was detected between response and CD4+ cell count, neutrophil count or ACTG risk category. Median quality-of-life scores improved during treatment in 2 studies which included prospective quality-of-life analysis. Liposomal doxorubicin produced better response rates than bleomycin and vincristine (BV) or standard doxorubicin plus bleomycin and vincristine (ABV) in 4 studies. In the 2 largest studies (n=218 and 225), liposomal doxorubicin was significantly more effective than ABV (response rates of 43 and 25%, respectively) or BV (59 and 23%, respectively). Extensive and progressive baseline disease in patients in these studies and/or more rigorously applied response criteria may have contributed to the low overall response rates observed in both treatment arms. More liposomal doxorubicin-than BV-treated patients completed 6 cycles of chemotherapy. Compared with these 2 large studies, response rates in 2 smaller studies which compared liposomal doxorubicin with BV chemotherapy in patients with Kaposi’s sarcoma were higher, but significant between-treatment differences were not observed. Patient numbers in the latter 2 studies may have been too small to detect significant differences. The reported duration of response to liposomal doxorubicin in the 2 largest comparative studies was 15 and 20 weeks. Between-treatment differences in response duration were not detected in any study. Liposomal doxorubicin is generally well tolerated. The most common dose-limiting adverse effect of the drug in patients with AIDS and Kaposi’s sarcoma is myelosuppression. At recommended dosages, neutropenia occurred in 50% of patients; severe neutropenia (<0.5 × 109 cells/L) occurred in 14%. However, pre-existing immune system compromise complicates assessment of neutropenia and infectious events in patients with AIDS. Anaemia occurred in 19% of patients. Palmar-plantar erythrodysaesthesia, characterised by ulceration, erythema and desquamation on the palms of the hands and soles of the feet with pain and inflammation, occurs in some patients, most commonly after 6 to 8 weeks of treatment. At recommended dosages of liposomal doxorubicin, the incidence of this syndrome is <5%. Although reactions may occasionally be severe and debilitating, they are more often mild; most patients with the syndrome do not require dosage reduction or prolonged treatment delay. Few data are available on the cardiac tolerability of liposomal doxorubicin. Although left ventricular failure has been reported in patients who received a high cumulative liposomal doxorubicin dose, some evidence suggests that the incidence and severity of this effect are lower than after similar doses of standard doxorubicin. Nausea was reported in 17 to 31% of patients; vomiting occurred in approximately 8% of patients. WHO grade III or IV nausea and vomiting occurred in approximately 5% of liposomal doxorubicin-treated patients in 1 study. Some patients experience acute hypersensitivity reactions during the initial few minutes of the first infusion of liposomal doxorubicin, but these reactions often do not prevent further treatment with the drug. Patients who do not experience infusion reactions during the first cycle of liposomal doxorubicin are unlikely to react to subsequent cycles. In contrast to standard doxorubicin, extravasation of liposomal doxorubicin has been associated with only transient and mild local irritation. Compared with BV chemotherapy, liposomal doxorubicin was associated with higher rates of myelosuppression and opportunistic infection, but lower rates of peripheral nerve toxicity. Limited data suggest that, when haemopoietic growth factor administration is permitted, myelosuppression is similar after liposomal doxorubicin and ABV chemotherapy. For patients with AIDS-related Kaposi’s sarcoma, the recommended dosage of liposomal doxorubicin (expressed in terms of doxorubicin content) is 20 mg/m2 every 3 weeks as long as response continues. In several large clinical studies, liposomal doxorubicin was administered at 2-week intervals. Dosage reduction is suggested for patients with treatment-limiting neutropenia, stomatitis or palmar-plantar erythrodysaesthesia.
TL;DR: The hypothesis that a novel energy‐dependent protein is responsible for the efflux in the AdVp cells is supported, and an eightfold overexpression of the alpha subunit of the Na+ channel in the resistant subline is demonstrated, which may be linked to the mechanism of drug resistance in the adsorption cells.
Abstract: MCF-7 human breast cancer cells selected in Adriamycin in the presence of verapamil developed a multidrug resistant phenotype, which was characterized by as much as 100,000-fold resistance to mitoxantrone, 667-fold resistance to daunorubicin, and 600-fold resistance to doxorubicin. Immunoblot and PCR analyses demonstrated no increase in MDR-1 or MRP expression in resistant cells, relative to parental cells. This phenotype is similar to one previously described in mitoxantrone-selected cells. The cells, designated MCF-7 AdVp, displayed a slower growth rate without alteration in topoisomerase IIα level or activity. Increased efflux and reduced accumulation of daunomycin and rhodamine were observed when compared to parental cells. Depletion of ATP resulted in complete abrogation of efflux of both daunomycin and rhodamine. No apparent alterations in subcellular daunorubicin distribution were observed by confocal microscopy. No differences were noted in intracellular pH. Molecular cloning studies using DNA differential display identified increased expression of the alpha subunit of the amiloride-sensitive sodium channel in resistant cells. Quantitative PCR studies demonstrated an eightfold overexpression of the alpha subunit of the Na+ channel in the resistant subline. This channel may be linked to the mechanism of drug resistance in the AdVp cells. The results presented here support the hypothesis that a novel energy-dependent protein is responsible for the efflux in the AdVp cells. Further identification awaits molecular cloning studies. J. Cell. Biochem. 65:513–526. © 1997 Wiley-Liss Inc.
TL;DR: In summary, epirubicin has an established role in the treatment of both early and advanced breast cancer and incombination with other highly active agents or in dose intensified regimens administered with haemopoietic growth factor and/or peripheral blood progenitor cell support may play a significant role in emerging breast cancer treatment strategies.
Abstract: Epirubicin, an anthracycline antitumour antibiotic which is structurally related to doxorubicin, is among the most active single agents used in the management of patients with breast cancer. The drug may be administered alone or in combination with other agents both to patients with early breast cancer and to those with metastatic disease. There is a clear relationship between epirubicin dose and tumour response. Dose intensified regimens have produced improved response rates in patients with advanced breast cancer compared with standard dose therapy; however, improved overall survival has not yet been demonstrated. The combination of epirubicin with newer agents such as vinorelbine or paclitaxel shows considerable promise, as does the use of epirubicin in high dose regimens with peripheral blood progenitor cell support. The major adverse effects of epirubicin are acute dose-limiting haematological toxicity and cumulative dose-related cardiac toxicity. These effects are less severe after epirubicin administration than after equimolar doses of doxorubicin. Other major adverse effects of epirubicin administration include mucositis, nausea and vomiting, reversible alopecia and local cutaneous and vesicant reactions. In summary, epirubicin has an established role in the treatment of both early and advanced breast cancer. Incombination with other highly active agents or in dose intensified regimens administered with haemopoietic growth factor and/or peripheral blood progenitor cell support, epirubicin may play a significant role in emerging breast cancer treatment strategies.
TL;DR: This study tested the therapeutic efficacy of doxorubicin hydrochloride in two formulations: free in saline suspension and encapsulated in polyethylene glycol-coated, long-circulating liposomes, finding liposome-encapsulation was significantly more effective in inhibiting tumour growth and in effecting cures.
Abstract: This study tested the therapeutic efficacy of doxorubicin hydrochloride in two formulations: free in saline suspension and encapsulated in polyethylene glycol-coated, long-circulating liposomes. The drug formulations at a dose level of 3 mg doxorubicin per kg body weight were injected intravenously to treat the human pancreatic carcinoma AsPC-1, implanted s.c. into nude Swiss mice. Liposome-encapsulated doxorubicin was significantly more effective in inhibiting tumour growth and in effecting cures, and had only minor systemic toxic side-effects, indicated by a transient weight loss. Confocal laser scanning microscopy was used to determine the tumour uptake and the clearance of doxorubicin in the free and in the liposomal forms. The liposome-encapsulated doxorubicin entered the tumour in greater quantity, and remained in the tumour longer, than the free drug. The liposome formulation produced a sixfold or greater increase in doxorubicin at the disease site. It is probable that increased penetration into the tumour, and long presence with slow drug release from liposomes in the tumour, account for the enhanced therapeutic effect when the drug was encapsulated in polyethylene glycol-coated liposomes.
TL;DR: Investigations on the modes of delivery and of action indicate that DaunoXome® arrives at and accumulates within tumor cells primarily in an intact form and increases in vivo daunorubicin tumor delivery by about 10-fold over conventional drug, yielding a comparable increase in therapeutic efficacy.
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TL;DR: Therapeutic studies demonstrated that increased tumor drug uptake observed for the liposomal doxorubicin formulations led to marginal improvements in antitumor activity, and it is suggested that much of the drug delivered inliposomal form is not biologically available.
Abstract: Murine fibrosarcoma tumors arising from subcutaneous inoculation of FSa-N cells exhibit 4-fold higher tumor-associated macrophage (TAM) levels than those from the FSa-R line. These solid tumors were used to assess the role of TAMs in the accumulation of liposomal anticancer drugs. Two liposomal formulations of doxorubicin were investigated: a conventional formulation composed of distearoylphosphatidylcholine (DSPC) and cholesterol and a sterically stabilized liposomal formulation composed of DSPC/cholesterol/poly (ethylene glycol)-modified distearoylphosphatidyethanolamine (PEG-PE). Circulating concentrations of PEG-PE containing liposomes 24 h after i.v. administration were 3-fold greater than those observed after administration of conventional liposomes. No differences were observed in drug retention or tumor (FSa-R or FSa-N) drug and liposomal lipid delivery when comparisons were made between different liposomal formulations. However, tumor doxorubicin concentrations were increased as much as 4-fold for liposomal formulations relative to free drug. Further, there was a 1.5- to 2-fold increase in doxorubicin delivery to TAM-enriched FSa-N tumors compared with FSa-R tumors. Fluorescence microscopy studies revealed a poor correlation between CD11b (Mac-1) positive cells (TAMs) and the appearance of doxorubicin fluorescence. These results suggest that uptake of liposomal drugs by TAMs does not account for the enhanced accumulation of liposomal drugs in solid tumors. Rather, the increased tumor drug delivery may be related to alternative TAM-mediated processes that increase tumor vascular permeability. Therapeutic studies demonstrated that increased tumor drug uptake observed for the liposomal doxorubicin formulations led to marginal improvements in antitumor activity, and it is suggested that much of the drug delivered in liposomal form is not biologically available.
TL;DR: Gemcitabine is an important agent for the management of several relatively chemoresistant cancer types, both with respect to anti-tumor activity and clinical benefit, and future research on combination studies deserves high priority considering the high response rates in NSCLC and bladder cancer.
Abstract: Gemcitabine (2′,2′-difluorodeoxycytidine, Gemzar) is a deoxycytidine analog with excellent antitumor activity against a number of solid tumors. Gemcitabine needs to be activated by deoxycytidine kinase and other kinases to its triphosphate, gemcitabine triphosphate, which can be incorporated into RNA and DNA. The latter effect is considered to be responsible for its antitumor effect and causes masked chain termination and inhibition of DNA repair. This effect may be of importance for combination with DNA interacting agents. In phase I trials daily, twice weekly, weekly and every two weeks schedules have been evaluated. At the weekly schedule of 1,000-1,250 mg/m 2 significant antitumor activity was observed in bladder, breast, ovary, and pancreatic cancer, non-small cell lung cancer (NSCLC), and small cell lung cancer of 31%, 33%, 22%, 11%, 22% and 27% total response rates, respectively. Gemcitabine also showed considerable improvement in clinical symptoms, while toxicity was not severe with mild myelosuppression. Due to its ability to inhibit DNA replication, combination studies were initiated with DNA damaging agents. For the various combinations with cisplatin in phase II studies on NSCLC, response rates varied from 42%-54%, with a median survival of generally more than 12 months. Also, combinations with taxanes, etoposide, doxorubicin and vindesin seem promising. Gemcitabine is an important agent for the management of several relatively chemoresistant cancer types, both with respect to antitumor activity and clinical benefit. Future research on combination studies deserves high priority considering the high response rates in NSCLC and bladder cancer. The Oncologist 1997;2:127-134
TL;DR: A number of drug delivery systems have been developed in order to improve therapeutic response and reduce toxicity to normal tissues, including the use of liposomal preparations.
TL;DR: In view of the cell cycle characteristics of prostate cancer, there appears to be an emerging role for combination inhibitors of mitosis, including estramustine in combination with the vinca alkaloids, etoposide or paclitaxel.
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TL;DR: PSC plasma concentrations that can revert multidrug resistance in experimental models could be achieved in patients who have solid tumors and who are treated with doxorubicin, however, a marked pharmacological interaction was found between doxorbicin and PSC, which led to substantial increase in hematological toxicity and required marked reduction of the doxOrubic in dose.
Abstract: Forty-two patients with advanced solid tumors were entered into a dose-finding study of the combination of doxorubicin with the cyclosporin analogue SDZ PSC 833 (PSC), given by oral route. Patients received PSC at escalating doses, ranging from 2.5 to 25 mg/kg/day, for 5 days, in doses given every 12 h. Doxorubicin was given by i.v. push on day 3 of PSC administration, 4 h after the morning dose of PSC. Pharmacokinetic analyses of PSC and doxorubicin were performed. A total of 38 patients received a combination of PSC and doxorubicin, and 27 received doxorubicin alone in the first course. The major toxicity of the combination was hematological and was significantly more severe than that with doxorubicin alone; severe myelosuppression was already observed at the first PSC dose level, which required doxorubicin dose reduction from 50 to 35 mg/m2. At all dose levels of PSC, up to 17.5 mg/kg/day, there were at least two patients with grade 3 or 4 hematological toxicity, which was manageable in less heavily pretreated patients. A further PSC dose escalation was performed to 25 mg/kg/day, together with doxorubicin, at a further reduced dose of 20 mg/m2. At this dose, central nervous system toxicity became the most relevant side effect. The increase of toxicity in the combined treatment was supported by a significant increase of the area under the plasma concentration-time curve to infinity of doxorubicin (54%) and a 10-fold increase of the area under the plasma concentration-time curve to infinity of doxorubicinol. The pharmacological interaction was not dependent on the plasma concentration of PSC. The total body clearance of doxorubicin decreased by 30%. PSC plasma concentrations of >1 microM at the time of doxorubicin administration were, in general, found at a dose of 7.5 mg/kg/day or higher. One patient had a partial response. In conclusion, PSC plasma concentrations that can revert multidrug resistance in experimental models could be achieved in patients who have solid tumors and who are treated with doxorubicin. However, a marked pharmacological interaction was found between doxorubicin and PSC, which led to substantial increase in hematological toxicity and required marked reduction of the doxorubicin dose. Further study of PSC may be warranted, in association with the investigation of P-glycoprotein expression and concentration of drugs in the tumor tissues.