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Biomedical subjects

A E Giuliano

Publications and source records attributed to A E Giuliano.

At least 19 recordsLinked to original sources
PubMed2001

Detection of occult metastatic breast cancer cells in blood by a multimolecular marker assay: correlation with clinical stage of disease.

Currently, molecular markers offer the unique opportunity to identify occult metastasis in early stage cancer patients not otherwise detected with conventional staging techniques. To date, well-characterized molecular tumor markers to detect occult breast cancer cells in blood are limited. Because breast tumors are heterogeneous in tumor marker expression, we developed a "multimarker" reverse transcription-PCR assay combined with the highly sensitive electrochemiluminescence automated detection system. Breast cancer cell lines (n = 7), primary breast tumors (n = 25), and blood from normal donors (n = 40) and breast cancer patients [n = 65; American Joint Committee on Cancer (AJCC) stages I-IV] were assessed for four mRNA tumor markers: beta-human chorionic gonadotropin (beta-hCG), oncogene receptor (c-Met), beta 1-->4-N-acetylgalactosaminyl-transferase, and a tumor-associated antigen (MAGE-A3). None of the tumor markers were expressed in any normal donor bloods. Breast cancer cell lines and primary breast tumors expressed beta-hCG, c-Met, beta 1-->4-N-acetylgalactosaminyl-transferase, and MAGE-A3 mRNA. Of the 65 breast cancer patient blood samples assessed, 2, 3, 15, 49, and 31% expressed 4, 3, 2, 1, and 0 of the mRNA tumor markers, respectively. At least two markers were expressed in 20% of the blood specimens. The addition of a combination of markers enhanced detection of systemic metastasis by 32%. In patient blood samples, the MAGE-A3 marker correlated significantly with tumor size (P = 0.0004) and AJCC stage (P = 0.007). The combination of beta-hCG and MAGE-A3 mRNA markers correlated significantly with tumor size (P = 0.04), and the marker combination c-Met and MAGE-A3 showed a significant correlation with tumor size (P = 0.005) as well as AJCC stage (P = 0.018). A multimarker reverse transcription-PCR assay that correlates with known clinicopathological prognostic parameters may have potential clinical utility by monitoring tumor progression with a blood test.

Adult↗
PubMed2001

Detection of MAGE-A3 in breast cancer patients' sentinel lymph nodes.

The detection of occult metastatic breast cancer cells by RT-PCR is limited by the poor specificity of most tumour mRNA markers. MAGE-A3 is a highly specific tumour mRNA marker that is not expressed in non-cancer cells. This study assesses MAGE-A3 mRNA as a molecular marker for the detection of tumour cells in the sentinel lymph nodes (SLN) of breast cancer patients. Serial frozen sections of SLN (n = 121) were obtained from 77 AJCC (American Joint Committee on Cancer) Stage I-IIIA breast cancer patients. MAGE-A3 mRNA analysis of SLN was performed by RT-PCR and Southern blot analysis. Tumour cells were detected in 48 of 121 (40%) SLN from 77 patients by H&E or IHC staining, and 35 of 77 (45%) patients, overall, had histopathologically (H&E and/or IHC) positive SLN. Among histopathologically negative SLN, 28 of 73 (38%) SLN were MAGE-A3 mRNA positive by RT-PCR. Overall, 41 of 77 (53%) patients and 50 of 121 (41%) SLN were positive for MAGE-A3. MAGE-A3 mRNA expression in the SLN occurred more frequently with infiltrating lobular carcinoma (P < 0.001) than with infiltrating ductal carcinoma, adding further evidence of possible phenotypic differences between these 2 subtypes of breast cancer. Due to its high specificity, MAGE-A3 mRNA is a potentially useful marker for detecting breast cancer cells in the SLN. One half of breast tumours expressed MAGE-A3 mRNA, which has important potential implications for antigen-specific targeted immunotherapy.

Adult↗
PubMed2001

Pathologic examination of sentinel lymph node for breast carcinoma.

Comprehensive pathologic evaluation of the sentinel lymph node using step sections and cytokeratin immunohistochemistry enhances detection of micrometastases and optimizes the staging of breast carcinoma. This review discusses our current understanding of the pathologic and molecular techniques for sentinel node examination.

Breast Neoplasms↗
PubMed2001

Long-term management and outcome of parathyroidectomy for sporadic primary multiple-gland disease.

HYPOTHESIS: For a specific subset of patients with sporadic primary multiple-gland parathyroid disease, subtotal parathyroidectomy results in long-term normocalcemia in the majority of patients, with a minimal complication rate. DESIGN: Retrospective analysis of outcomes in patients undergoing parathyroidectomy performed by a single surgeon (A.E.G.) between 1984 and 1999. SETTING: A multidisciplinary endocrine service based at a tertiary referral center. PATIENTS: Patients undergoing subtotal parathyroidectomy for primary hyperparathyroidism due to sporadic multiple-gland disease identified from a single surgeon's operative records (A.E.G.). MAIN OUTCOME MEASURES: Data analyzed included demographic factors, operative and pathologic findings, and postoperative and long-term clinical and laboratory results, including calcium and intact parathyroid hormone levels. RESULTS: Of 379 patients undergoing parathyroidectomy for hyperparathyroidism between 1984 and 1999, 49 (13%) had sporadic multiple-gland disease. Median preoperative calcium and intact parathyroid hormone (iPTH) levels were 2.7 mmol/L (10.8 mg/dL) and 11.79 pmol/L, respectively. Postoperative calcium and iPTH levels were available in 39 patients, and median values were 2.28 mmol/L (9.1 mg/dL) and 2.84 pmol/L, respectively. Long-term follow-up was available for 36 patients (73%), and duration ranged from 6 to 180 months (median, 44 months). Median calcium and iPTH levels at follow-up were 2.3 mmol/L (9.2 mg/dL) and 3.26 pmol/L, respectively, with 3 (8%) of 36 patients having evidence of persistent or recurrent hyperparathyroidism. No patient had biochemical evidence of hypoparathyroidism at long-term follow-up. Five patients (14%) had persistent elevated iPTH levels (range, 8.11-10.95 pmol/L) and normal calcium levels. CONCLUSIONS: Subtotal parathyroidectomy for sporadic primary multiple-gland disease resulted in a long-term normocalcemia rate of 92%, with minimal complications. Selective subtotal parathyroidectomy can yield excellent long-term results in patients with multiple-gland disease.

Adult↗
PubMed2001

Lymphoscintigraphy and lymphatic mapping for identification of sentinel lymph nodes.

The recently introduced technique of sentinel lymph node dissection (SLND) may replace complete axillary lymph node dissection for axillary staging of early breast cancer. Successful SLND is predicated on meticulous delineation of the lymphatic pathway and sentinel node(s). Currently employed lymphatic mapping materials include vital blue dyes and radioactive tracers. Techniques of intraoperative lymphatic mapping and SLND using dye, tracer, or both have high success rates in the hands of experienced investigators, but their routine and widespread use awaits resolution of questions about the timing, dose, and type of radioactive tracer; the optimal lymphatic mapping technique; indications and contraindications for SLND; and certification of qualified surgeons, pathologists, and nuclear medicine physicians.

Breast Neoplasms↗
PubMed2001

Taxol-induced ceramide generation and apoptosis in human breast cancer cells.

PURPOSE: Taxol has emerged as a valuable antimitotic chemotherapeutic agent, particularly in advanced breast and ovarian cancers. Although much is known about cytotoxic mechanisms, the effectiveness of Taxol cannot be solely explained by microtubular interaction. This study was undertaken to determine whether ceramide generation plays a role in Taxol-induced apoptosis. METHODS: Hormone-independent MDA-MB-468 and hormone-dependent MCF-7 breast cancer cell lines were employed, and ceramide metabolism was characterized using [3H]palmitic acid as lipid precursor. RESULTS: Exposure of cells to Taxol resulted in enhanced formation of [3H]ceramide. Ceramide increased nearly 2-fold in MDA-MB-468 cells exposed to 50 nM Taxol, and more than 2.5-fold in MCF-7 cells exposed to 1.0 microM Taxol. These concentrations mirrored the EC50 (amount of drug eliciting 50% cell kill) for Taxol in the two cell lines. Use of cell-permeable C6-ceramide as a medium supplement revealed that MDA-MB-468 cells were 20-fold more sensitive to ceramide than MCF-7 cells (P < 0.001). Ceramide was generated as early as 6 h after exposure to Taxol in MDA-MB-468 cells, whereas the earliest signs of apoptosis were detected 12 h after treatment, and by 24 h the apoptotic index was six times that of untreated cells. Both fumonisin B1, a ceramide synthase inhibitor, and L-cycloserine, a serine palmitoyltransferase inhibitor, blocked Taxol-induced ceramide generation, whilst sphingomyelin levels remained unchanged, indicating a de novo pathway of ceramide formation. L-Cycloserine reduced Taxol-induced apoptosis by 30% in MDA-MB-468 cells and totally blocked Taxol-induced apoptosis in MCF-7 cells. CONCLUSIONS: These results suggest that Taxol-induced apoptosis is, in part, attributable to ceramide and sphingoid bases. This is of relevance to drug mechanism studies, as ceramide is a known messenger of apoptosis. Clinical use of Taxol with ceramide-enhancing agents may maximize cytotoxic potential.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Dermal versus intraparenchymal lymphoscintigraphy of the breast.

BACKGROUND AND OBJECTIVE: Dermal and intraparenchymal (IP) injections of radiocolloid have been used for lymphoscintigraphic identification of the sentinel node (SN) in breast cancer. Because of our institute's extensive experience with dermal and IP lymphoscintigraphy for melanoma and breast cancer, we compared patterns of lymphatic migration after both types of injections to identify any differences in drainage patterns or SN identification. METHODS: Lymphoscintigrams (n = 31) after dermal injections in 30 patients with primary cutaneous melanoma on the breast were compared with lymphoscintigrams after IP injections in 97 consecutive patients with breast cancer. In each case, 400 microCi of filtered 99mTc-sulfur colloid was injected in four quadrants around the tumor or in the biopsy cavity. All lymphoscintigrams were reviewed for patterns of migration and SN location. RESULTS: Five of 31 (16%) dermal injections demonstrated bilateral axillary migration (n = 3) or a suprasternal SN (n = 2), neither of which was found with IP injections. Conversely, 3 of 97 (3%) IP injections demonstrated direct supraclavicular (n = 2) or costal margin (n = 1) nodes (P = .006), neither of which was found with dermal injections. Low axillary SNs were noted after 26 (84%) dermal and 93 (96%) IP injections (P = .037). The incidence of extra-axillary SNs was 26% (8 of 31) in the dermal group but only 5% (5 of 97) in the IP group (P = .0027). CONCLUSION: There is a significant difference in lymphatic drainage and SN localization between dermal and IP lymphoscintigraphy. This finding has implications for injection techniques when lymphatic mapping of the SN is undertaken to stage a breast carcinoma.

Axilla↗
PubMed2001

Role for sentinel lymph node dissection in the management of large (> or = 5 cm) invasive breast cancer.

BACKGROUND: Sentinel lymph node dissection (SLND) for small, early-stage breast cancer is well accepted. However, the role of SLND for large primary breast cancer is controversial. We investigated the feasibility and clinical applicability of SLND in patients with large (> or = 5 cm) breast cancers and clinically negative axillae. METHODS: A prospectively entered database was used to identify all patients who underwent surgical management of histopathologically confirmed primary breast carcinomas > or = 5 cm in diameter between September 1991 and August 2000. Patients who had clinically negative axillae and underwent SLND followed by completion axillary lymph node dissection (ALND) were selected for the study. The positivity rate, accuracy rate, and false-negative rate of SLND were determined. RESULTS: Of the 41 patients selected for the study, 24 had infiltrating ductal carcinoma and 17 had infiltrating lobular carcinoma. Mean tumor size was 7.12 cm (range, 5-23 cm). At least one sentinel lymph node (SLN) was identified in all cases. Thirty patients had tumor-positive SLNs. Axillary metastasis was also identified in one patient who did not have a positive SLN. Thus, SLN status accurately predicted regional nodal status in 98% (40 of 41) of cases. The false-negative rate of SLND was 3% (1 of 31). None of the three patients with SLN micrometastasis, defined as a tumor focus < or = 2 mm, had tumor deposits in nonsentinel axillary lymph nodes. Only SLN macrometastasis (> 2-mm tumor deposit) and primary tumor size > or = 7 cm predicted nonsentinel axillary metastasis with significance on multivariate analysis (P = .008 and P = .046, respectively). CONCLUSIONS: SLND is feasible and accurate in patients with large breast cancers and clinically negative axillae. Axillary lymph node dissection can be avoided in nearly one third of patients by focused examination of the SLN.

Adult↗
PubMed2001

Surgical management of breast cancer in the elderly patient.

BACKGROUND: Breast cancer in the older woman is a major health issue and therapeutic challenge. This study asked if presentation, surgical treatment, and outcome of breast cancer are different in elderly women compared with their younger counterparts. METHODS: There were 816 women < 70 years (younger) and 190 > or = 70 years (older) treated surgically for breast carcinoma between January 1992 and April 2000. Data for younger and older patients was analyzed from our prospective database. RESULTS: More older women had mammographic lesions (P < 0.006). Breast conservation was the treatment of choice for both groups. Stage, tumor size, histology and disease-specific survival were similar for both. There was no evidence of disease in 93% of cases in the < 70 years group at median follow-up of 38.4 months and 91% for the > or = 70 years group at 44.5 months. CONCLUSIONS: In our population the presentation, surgical treatment, and survival from breast cancer is similar in older and younger women.

Adult↗
PubMed2001

The use of sentinel lymphadenectomy to identify candidates for postoperative adjuvant therapy of melanoma and breast cancer.

Sentinel lymphadenectomy (SLND) is fast becoming the procedure of choice for staging primary breast carcinoma and melanoma. This simpler and less morbid alternative to standard lymph node dissection can increase the rate of detecting nodal disease. Because the tumor status of the regional lymph nodes remains a significant prognostic tool in both diseases, clinicians may use SLND to facilitate selection of patients for adjuvant chemotherapy. Although SLND has been validated by institutions worldwide, it continues to evolve. The following review will examine current data and controversies surrounding this emerging technology.

Antineoplastic Agents↗
PubMed2001

Hepatic cytoreduction followed by a novel long-acting somatostatin analog: a paradigm for intractable neuroendocrine tumors metastatic to the liver.

BACKGROUND: Optimal management of symptomatic neuroendocrine tumors that metastasize to the liver is controversial. We investigated aggressive hepatic cytoreduction and postoperative administration of octreotide long-acting release (LAR), a long-acting somatostatin analog. METHODS: Between December 1992 and August 2000, 31 patients underwent hepatic surgical cytoreduction (20 carcinoid, 10 islet cell, and 1 medullary). All patients had progressive symptoms refractory to conventional therapy. RESULTS: Hepatic cytoreduction (resection, cryosurgery, and/or radiofrequency ablation) eliminated symptoms in 27 patients (87%) and decreased secretion of hormones by an overall mean of 59%. When minor symptoms returned and/or hormonal levels increased during follow-up, adjuvant therapy was started. Ten patients received adjuvant octreotide LAR once a month, and 21 received other adjuvants. At a median postoperative follow-up of 26 months, 16 patients had progressive/recurrent disease, 13 had died of their disease, and 2 remained free of disease. Median symptom-free interval was 60 months (95% confidence interval, 48-72) with octreotide LAR and 16 months (95% confidence interval, 10-29) with other adjuvants (P = .0007). Two-year symptom-free survival rate was 100% with octreotide LAR and 33% with other adjuvants. CONCLUSIONS: Hepatic surgical cytoreduction can palliate progressive symptoms associated with liver metastases from intractable neuroendocrine tumors. Postoperative adjuvant therapy with octreotide LAR can prolong symptom-free survival.

Adult↗
PubMed2001

Ceramide glycosylation potentiates cellular multidrug resistance.

Ceramide glycosylation, through glucosylceramide synthase (GCS), allows cellular escape from ceramide-induced programmed cell death. This glycosylation event confers cancer cell resistance to cytotoxic anticancer agents [Liu, Y. Y., Han, T. Y., Giuliano, A. E., and M. C. Cabot. (1999) J. Biol. Chem. 274, 1140-1146]. We previously found that glucosylceramide, the glycosylated form of ceramide, accumulates in adriamycin-resistant breast carcinoma cells, in vinblastine-resistant epithelioid carcinoma cells, and in tumor specimens from patients showing poor response to chemotherapy. Here we show that multidrug resistance can be increased over baseline and then totally reversed in human breast cancer cells by GCS gene targeting. In adriamycin-resistant MCF-7-AdrR cells, transfection of GCS upgraded multidrug resistance, whereas transfection of GCS antisense markedly restored cellular sensitivity to anthracyclines, Vinca alkaloids, taxanes, and other anticancer drugs. Sensitivity to the various drugs by GCS antisense transfection increased 7- to 240-fold and was consistent with the resumption of ceramide-caspase-apoptotic signaling. GCS targeting had little influence on cellular sensitivity to either 5-FU or cisplatin, nor did it modify P-glycoprotein expression or rhodamine-123 efflux. GCS antisense transfection did enhance rhodamine-123 uptake compared with parent MCF-7-AdrR cells. This study reveals that GCS is a novel mechanism of multidrug resistance and positions GCS antisense as an innovative force to overcome multidrug resistance in cancer chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Microsatellite alterations detected in the serum of early stage breast cancer patients.

Breast cancer is the most common malignancy affecting women. Advances in screening have resulted in an increasing trend towards detecting earlier stage tumors associated with a longer disease-free survival. Because of this prolonged latency period, it is critical to identify patients early in their disease course who are at increased risk for recurrence, whereby treatment decisions may be altered accordingly based on more precise information. Molecular markers that demonstrate prognostic importance as well as utility for assessing subclinical disease progression offer one such approach. Specifically, circulating microsatellite alterations that reflect those genetic events occurring in tumors and that can be serially assessed through a minimally invasive procedure are a logistically practical method. In this study, serum was collected preoperatively from 56 patients with early stage breast cancer (AJCC stages I/II) and assessed for loss of heterozygosity (LOH) using 8 microsatellite markers. Twelve (21%) of 56 patients demonstrated LOH in their serum for at least one marker. Histopathologic correlation revealed an association between the presence of circulating LOH in serum and those tumors with increased proliferation indices as characterized by an increased diploid index, elevated MIB-1 fraction, and abnormal ploidy. These findings demonstrate the presence of circulating microsatellite alterations in the serum from patients with early stage breast cancer. The association of known poor prognostic features found in tumors with increased nuclear activity not only suggests a possible etiology for their presence, but also offers a potential blood-based surrogate marker for this disease that may demonstrate clinical utility in long-term follow-up studies.

Breast Neoplasms↗
PubMed2001

Current status of sentinel lymphadenectomy in breast cancer.

Investigators at many cancer centers have verified that the sentinel node (SN) is the first lymph node to receive lymphatic drainage from a primary breast cancer and therefore the node most likely to contain metastatic tumor cells. When sentinel lymph node dissection (SLND) is undertaken by an experienced multidisciplinary team, the finding of a tumor-free SN almost invariably indicates that the patient has node-negative breast cancer and need not undergo further axillary dissection. At the present time, however, only centers with experience in SLND may abandon completion axillary lymphadenectomy when the SN is free of tumor. In other settings, level I and II axillary dissection is essential until the SLND team has achieved consistently accurate results and the institution has established excellent quality control.

Breast Neoplasms↗
PubMed2000

Pathologic features associated with nonsentinel lymph node metastases in patients with metastatic breast carcinoma in a sentinel lymph node.

BACKGROUND: To the authors' knowledge it has not yet been determined which patients with primary breast carcinoma and an axillary sentinel lymph node (SN) metastasis have additional metastases in nonsentinel lymph nodes. METHODS: Pathologic features of the primary breast carcinoma and its SN metastasis were examined in 194 patients and correlated with the tumor status of the non-SNs in the same axillary basin. Two-level cytokeratin immunohistochemistry was applied to the SNs and to non-SNs of cases that were negative by standard hematoxylin and eosin examination. RESULTS: Lymph node staging based on SN findings, size of the primary tumor, and presence of peritumoral lymphatic vascular invasion (LVI) were associated with non-SN metastasis. The majority (63%) of the 101 patients with SN macrometastases had non-SN metastases. Extranodal hilar tissue invasion in conjunction with SN involvement also was strongly associated with non-SN metastasis (P = 0.0001) but was present in only 65% of patients (35 of 54 patients) with non-SN macrometastases. Approximately 26% of patients (24 of 93 patients) with SN micrometastases (</= 2.0 mm) had non-SN metastases; among these patients only primary tumor size and peritumoral LVI were correlated with non-SN metastasis. CONCLUSIONS: Detailed pathologic examination of the primary tumor and its SN metastasis may increase precision in the selection of patients for further axillary surgery or radiation therapy.

Adult↗
PubMed2000

Uncoupling ceramide glycosylation by transfection of glucosylceramide synthase antisense reverses adriamycin resistance.

Previous work from our laboratory demonstrated that increased competence to glycosylate ceramide conferred adriamycin resistance in MCF-7 breast cancer cells (Liu, Y. Y., Han, T. Y., Giuliano, A. E. , and M. C. Cabot. (1999) J. Biol. Chem. 274, 1140-1146). This was achieved by cellular transfection with glucosylceramide synthase (GCS), the enzyme that converts ceramide to glucosylceramide. With this, we hypothesized that a decrease in cellular ceramide glycosylation would result in heightened drug sensitivity and reverse adriamycin resistance. To down-regulate ceramide glycosylation potential, we transfected adriamycin-resistant breast cancer cells (MCF-7-AdrR) with GCS antisense (asGCS), using a pcDNA 3.1/his A vector and developed a new cell line, MCF-7-AdrR/asGCS. Reverse transcription-polymerase chain reaction assay and Western blot analysis revealed marked decreases in both GCS mRNA and protein in MCF-7-AdrR/asGCS cells compared with the MCF-7-AdrR parental cells. MCF-7-AdrR/asGCS cells exhibited 30% less GCS activity by in vitro enzyme assay (19.7 +/- 1.1 versus 27.4 +/- 2.3 pmol GC/h/microg protein, p < 0.001) and were 28-fold more sensitive to adriamycin (EC(50), 0.44 +/- 0.01 versus 12.4 +/- 0.7 microM, p < 0. 0001). GCS antisense transfected cells were also 2.4-fold more sensitive to C(6)-ceramide compared with parental cells (EC(50) = 4. 0 +/- 0.03 versus 9.6 +/- 0.5 microM, p < 0.0005). Under adriamycin stress, GCS antisense transfected cells compared with parental cells displayed time- and dose-dependent increases in endogenous ceramide and dramatically higher levels of apoptotic effector, caspase-3. Western blotting showed that adriamycin sensitivity, introduced by asGCS gene transfection, was independent of P-glycoprotein and Bcl-2 expression. In summary, this work shows that transfection of GCS antisense tempers the expression of native GCS and restores cell sensitivity to adriamycin. Therefore, limiting the potential to glycosylate ceramide, which is an apoptotic signal in chemotherapy and radiotherapy, provides a promising approach to combat drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

SDZ PSC 833 the drug resistance modulator activates cellular ceramide formation by a pathway independent of P-glycoprotein.

SDZ PSC 833 (PSC 833) is a new multidrug resistance modulator. Recent studies have shown that the principal mechanism of action of PSC 833 is to bind P-glycoprotein (P-gp) and prevent cellular efflux of chemotherapeutic drugs. We previously reported that PSC 833 increases cellular ceramide levels. The present study was conducted to determine whether the impact of PSC 833 on ceramide generation is dependent on P-gp. Work was carried out using the drug-sensitive P-gp-deficient human breast adenocarcinoma cell line, MCF-7, and drug resistant MCF-7/MDR1 clone 10.3 cells (MCF-7/MDR1), which show a stable MDR1 P-gp phenotype. Overexpression of P-gp in MCF-7/MDR1 cells did not increase the levels of glucosylceramide, a characteristic which has been associated with multidrug resistant cells. Treatment of MCF-7 and MCF-7/MDR1 cells with PSC 833 caused similar ceramide elevation, in a dose-responsive manner. At 5.0 microM, PSC 833 increased ceramide levels 4- to 5-fold. The increase in ceramide levels correlated with a decrease in survival in both cell lines. The EC50 (concentration of drug that kills 50% of cells) for PSC 833 in MCF-7 and MCF-7/MDR1 cells was 7.2 +/- 0.6 and 11.0 +/- 1.0 microM, respectively. C6-Ceramide exposure diminished survival of MCF-7 cells; whereas, MCF-7/MDR1 cells were resistant to this short chain ceramide analog. Preincubation of cells with cyclosporine A, which has high affinity for P-gp, did not diminish the levels of ceramide generated upon exposure to PSC 833. These results demonstrate that PSC 833-induced cellular ceramide formation occurs independently of P-gp. As such, these data indicate that reversal of drug resistance by classical P-gp blockers may be modulated by factors unrelated to drug efflux parameters.

ATP Binding Cassette Transporter, Subfamily B, Mem↗