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Biomedical subjects

Y Tong

Publications and source records attributed to Y Tong.

At least 91 records · Page 5Linked to original sources
PubMed1995

Susceptibility of idarubicin, daunorubicin, and their C-13 alcohol metabolites to transport-mediated multidrug resistance.

The intracellular pharmacokinetics and cytotoxicity of idarubicin (IDA), daunorubicin (DNR), and their corresponding C-13 alcohol metabolites, idarubicinol (IDAol) and daunorubicinol (DNRol), were studied in drug-sensitive HL-60/W human leukemia cells, and in two multidrug-resistant (MDR) sublines, HL-60/Vinc (overexpress P-glycoprotein, Pgp) and HL-60/Adr (overexpress multidrug resistance-associated protein, MRP). Intracellular drug accumulation (1 micrograms/mL) and retention were measured by flow cytometry. Mean intracellular steady-state concentration (Css, fluorescence units/cell) and area under the intracellular drug concentration x time curve (AUC, Fl.U/cell.min) were calculated. Relative to the values for the respective drugs in HL-60/W cells, the Css and AUC of IDA were much higher than those of DNR in the MDR cell lines, with Css and AUC of IDAol intermediate between IDA and DNR. In the MDR cell lines, the MDR modulator cyclosporine A (CsA), in concentrations of 0.3 to 30 mumol/L, caused minimal effects on 3-hr IDA accumulation, intermediate enhancement of IDAol accumulation, and greatest enhancement of DNR accumulation. The MDR cell lines were much less resistant to IDA (3- to 16-fold) than to DNR (65- to 117-fold). This difference was not the result of IDA being more potent than DNR, since the sensitivity of HL-60/W cells to IDA differed from their sensitivity to DNR by < 2-fold. The cellular pharmacokinetics and cytotoxicity of IDA in MDR human breast carcinoma cells MCF-7/AdrVp, which overexpress the putative MDR transporter P-95, were far superior to those of DNR, and were comparable to these parameters for IDA in parental MCF-7/W cells. These studies demonstrate that the cellular pharmacology and cytotoxicity of IDA in MDR cell lines that overexpress MRP, Pgp, or P-95 are more advantageous than those of DNR, suggesting that IDA is less susceptible to the transport-mediated MDR mechanism manifested. IDA is not completely invulnerable to MDR, however, since the MDR sublines studied did display a demonstrable level of resistance to IDA, compared with their drug-sensitive counterparts. IDAol, the major plasma metabolite of IDA, demonstrated behavior intermediate between the MDR-susceptible drug DNR and its parent compound, suggesting that its cytotoxic action is subject to transport-mediated cellular defenses.(ABSTRACT TRUNCATED AT 400 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Recurrent varicose veins following high ligation of long saphenous vein: a duplex ultrasound study.

Duplex scanning was used to study recurrent varicose veins in 244 limbs with previous high ligation of the long saphenous vein. The recurrent varicose veins were classified into two types according to the presence or absence of a residual long saphenous vein. Varicose veins with a residual long saphenous vein (type I) occurred in 168 limbs (68.9%). A residual long saphenous vein with an incompetent saphenofemoral junction was present in 125 limbs and one without any residual saphenofemoral junction in 43 limbs. Besides the presence of an incompetent long saphenous vein in this group, an incompetent short saphenous vein was detected in 26 limbs, incompetent perforating vein(s) in 45 limbs and incompetent deep veins in 26 limbs. Varicose veins without a residual long saphenous vein (type II) occurred in 76 limbs (31.1%). An incompetent short saphenous vein was demonstrated in 44 limbs, incompetent perforating vein(s) in 18 limbs and incompetent deep veins in 32 limbs. Of the total 244 limbs with recurrent varicose veins, long saphenous vein incompetence was involved in 168 (68.9%), short saphenous vein incompetence in 70 (28.7%), perforating vein incompetence in 63 (25.8%) and deep venous incompetence in 58 (23.8%). Although saphenofemoral junction incompetence was found to be the main source of recurrence, a segment of incompetent residual long saphenous vein, an incompetent short saphenous vein, perforating vein and deep venous system incompetence are other common sources of recurrence. A precise assessment to identify underlying venous incompetence is important for the management of recurrent varicose veins.

Humans↗
PubMed1995

An etoposide-resistant lung cancer subline overexpresses the multidrug resistance-associated protein.

We have characterised an etoposide-resistant subline of the small-cell lung cancer cell line, UMCC-1, derived at our centre. Subline UMCC-1/VP was developed by culturing the parent line in increasing concentrations of etoposide over 16 months. UMCC-1/VP is 20-fold resistant to etoposide by MTT assays, relative to the parent line, and is cross-resistant to doxorubicin, vincristine and actinomycin D, but not to taxol, cisplatin, melphalan, thiotepa or idarubicin. Topoisomerase II immunoblotting demonstrates a 50% reduction of the protein in the resistant subline. The UMCC-1/VP subline demonstrates a marked decrease in the accumulation of [3H]etoposide relative to the parent line, as well as a modest reduction in the accumulation of daunorubicin. Reverse transcription-polymerase chain reaction assays demonstrate no detectable mdr1 expression but marked expression of the multidrug resistance-associated protein (MRP) gene in the resistant subline. Northern blotting with an MRP cDNA probe confirms marked overexpression of the MRP gene only in the UMCC-1/VP subline. Western blotting with antisera against MRP peptide confirms a 195 kDa protein band in the UMCC-1/VP subline. Southern blotting experiments demonstrate a 10-fold amplification of the MRP gene in the resistant subline. Depletion of glutathione with buthionine sulphoximine sensitised UMCC-1/VP cells to daunorubicin and etoposide. Our studies indicate that MRP gene expression may be induced by etoposide and may lead to reduced accumulation of the drug.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Normal mouse skin lymphocyte, Langerhans cell, and keratinocyte responses to intradermal injections of interferon-alpha and interferon-gamma.

To investigate the skin immune responses induced by intradermal injections of interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma), normal C3H mice were injected intradermally with murine recombinant interferon-alpha (rIFN-alpha), interferon-gamma (rIFN-gamma), or the combination of rIFN-alpha and rIFN-gamma, three times per week for 2 or 4 weeks. Contralateral sites were similarly injected with placebo (saline). The results showed that after 6 or 12 injections of rIFN-alpha (10,000 IU/per injection), epidermal ATPase+ and Ia+ Langerhans cells (LGs) decreased significantly (p < 0.01 and p < 0.05) but dermal lymphocytic infiltrates, including CD3+ (pan-T cells), L3T4+ (T helper cells), Lyt-2+ (T suppressor/cytotoxic cells), MOMA+ (macrophages and monocytes), and dermal Ia+ cells, increased significantly (p < 0.01) compared with both saline injection sites and untreated skin. In contrast to rIFN-alpha, 6 injections of 10,000 IU rIFN-gamma failed to induce significant changes in either epidermal LGs or dermal lymphocytic infiltrates, except for an increase in dermal MOMA+ cells. High-dose rIFN-gamma injections (50,000 IU) strongly enhanced the expression of Ia antigen in epidermal keratinocytes (KCs), increased dermal lymphocytic infiltrates, and decreased the LGs in a similar pattern to that of rIFN-alpha. Furthermore, rIFN-gamma (50,000 IU) injections induced Ia antigen expression on the KCs in the contralateral saline injection areas, suggesting a systemic effect. Injections of a combination of rIFN-alpha and rIFN-gamma failed to show synergism for induction of skin immune responses.

Adenosine Triphosphatases↗
PubMed1995

Duplex ultrasound assessment of the venous status of the swollen leg.

Between January 1991 and December 1993, duplex ultrasound characterization of venous disease in leg swelling was studied in 214 patients (261 limbs; 167 unilateral and 47 bilateral). All patients were examined with a duplex scanner, the superficial and deep venous systems were evaluated for the presence of thrombus and valvular incompetence. Of the 261 limbs, 29 (11.1%) had deep venous thrombosis, 14 (5.4%) had superficial venous thrombosis, 66 (25.3%) had deep venous incompetence (31/66 limbs also had superficial venous incompetence), 65 (24.9%) had incompetence in the superficial veins only, and five (1.9%) had deep venous obstruction resulting from a popliteal cyst or a popliteal vein ligation. Eighty-two limbs (31.4%) had no evidence of venous obstruction or incompetence at the areas evaluated. This study showed that venous obstruction and valvular incompetence had occurred in two-thirds of swollen legs examined. Some of the venous obstructions resulted from surgically treatable diseases such as a popliteal cyst, and some of the venous disorders involved the superficial venous system only. Complete venous evaluation with duplex imaging can be very helpful in the determination of the underlying cause of the swelling.

Adolescent↗
PubMed1995

Transforming growth factor alpha gene expression in cultured human keratinocytes is unaffected by cellular aging.

BACKGROUND: Cultured human keratinocyte grafts have been shown to stimulate endogenous reepithelialization of both chronic nonhealing and acute partial-thickness wounds. This effect is most likely mediated by cytokines that stimulate keratinocyte growth, such as transforming growth factor alpha. The effect of cellular age on cytokine expression by cultured grafts used for this purpose is presently undefined. In this study, transforming growth factor alpha gene expression in cultured foreskin keratinocytes from donors varying in age from 2 to 82 years was analyzed semiquantitatively by two separate methods, ie, Northern hybridization and competitive polymerase chain reaction. RESULTS: No pattern of decline in transforming growth factor alpha messenger RNA expression with increasing cellular age was observed by either analysis. CONCLUSION: The results indicate that expression of transforming growth factor alpha by cultured grafts may not be significantly affected by increasing cellular age and suggest that, even in the elderly, cultured autografts may be effective as pharmacologic agents for wound treatment.

Adult↗
PubMed1994

Identification of a novel protein tyrosine phosphatase with sequence homology to the cytoskeletal proteins of the band 4.1 family.

Use of the polymerase chain reaction (PCR) in conjunction with Southern hybridization, using probes corresponding to known phosphatase sequences, resulted in the identification of rat cDNA clones encoding a novel protein tyrosine phosphatase which was termed rPTP2E. The cDNAs comprise 5,543 bp and predict a polypeptide of 1175 amino acids possessing a single catalytic domain at its C-terminus. The N-terminal region of the deduced polypeptide displays high sequence homology to the cytoskeleton-associated proteins of the band 4.1 family. A variant form, termed rPTP2E1, was also identified which contains the catalytic domain only. rPTP2E and rPTP2E1 were expressed in various rat tissues, particularly abundantly in adrenal glands. The catalytic domain of PTP2E was expressed in Escherichia coli and was shown to possess specific protein tyrosine phosphatase activity. The identification of rPTP2E suggests the existence of a subfamily of band 4.1 domain-containing PTPs which may play an important role in signalling pathway and control of cytoskeletal integrity.

Amino Acid Sequence↗
PubMed1994

Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design.

BACKGROUND: Cisplatin-based induction chemotherapy may achieve a complete response (i.e., no sign of tumor following treatment) in 70%-80% of patients with germ cell tumors. However, only a minority of patients in whom the firstline regimens fail are cured with the salvage regimens. PURPOSE: The aim of these studies was to identify new agents or new regimens for the treatment of germ cell tumors by carrying out quantitative assessment in vitro of two promising new antitumor agents (paclitaxel [Taxol] and topotecan) and three more established agents (cisplatin, vincristine, and etoposide). These agents were used singly or in two- and three-drug combinations and were selected because they represent five distinct categories of antineoplastic mechanisms. METHODS: The combination index-isobologram method, which is based on the median-effect principle developed by Chou and Talalay, was used for computerized data analysis. This method was selected because it takes into account both the potencies of each drug and combinations of these drugs and the shapes of their dose-effect curves. RESULTS: Synergism against the growth of teratocarcinoma cells resistant to cisplatin (833K/64CP10 cells) was greater than against the growth of parent 833K cells. The degrees of synergism were in the following order: cisplatin + topotecan > or = paclitaxel + cisplatin + topotecan > paclitaxel + topotecan > or = paclitaxel + etoposide > paclitaxel + cisplatin + etoposide > paclitaxel + cisplatin. All other combinations showed nearly additive effects or moderate antagonism. The degrees of antagonism were as follows: cisplatin + etoposide > or = paclitaxel + vincristine > paclitaxel + cisplatin + vincristine > cisplastin + vincristine. The combination of paclitaxel and cisplatin was synergistic against 833K/64CP10 cells and moderately antagonistic against 833K cells. Since the combination of paclitaxel, cisplatin, and topotecan and the two-component combinations of these drugs (cisplatin + topotecan and paclitaxel + topotecan) showed synergism stronger than that of other combinations, these three drugs were selected for illustrating detailed data analysis, using a computer software program developed in this institute. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that, as a result of synergy, the doses of these agents needed to achieve an antitumor effect may be reduced by twofold to eightfold when these agents are given in combination. The present quantitative data analyses for synergism or antagonism provide a basis for a rational design of clinical protocols for combination chemotherapy in patients with advanced germ cell tumors.

Antineoplastic Agents↗
PubMed1994

Synergistic reversal of multidrug-resistance phenotype in acute myeloid leukemia cells by cyclosporin A and cremophor EL.

Cremophor (Crem) EL, the vehicle for intravenous delivery of cyclosporin A (CsA), has been reported to counteract multidrug resistance (MDR) in P-glycoprotein (Pgp)-over-expressing cell lines. Because of this, we sought to determine whether Crem functions independently as a modulator of MDR in blast cells obtained from acute myelogenous leukemia (AML) patients, and the nature of its interaction in combination with CsA in reversing an MDR phenotype. In the phenotypically classical MDR AML cell lines HL-60/Vinc (overexpresses Pgp) or HL-60/AR (does not overexpress Pgp), the dose causing half-maximum enhancement (D50) of daunorubicin (DNR, 1 micrograms/mL, 3 hours) accumulation was achieved by the combination of CsA and Crem (CsA/Crem) at 1.2 mumol/L CsA. In contrast, the D50 for Crem alone was approached at an amount that would be needed to suspend 6.2 mumol/L CsA for HL-60/Vinc, and 81 mumol/L CsA for HL-60/AR. The D50 concentrations for CsA alone (dissolved in ethanol, which does not alter DNR accumulation) were also higher than those for CsA/Crem, being 6.5 mumol/L for HL-60/Vinc, and 3.1 mumol/L for HL-60/AR. The maximum absolute level of enhancement of DNR accumulation (Emax) in each cell line was approximately equivalent for CsA/Crem or CsA alone, and was equal to the 3 hr intracellular DNR accumulation observed in parental, drug sensitive HL-60/W cells. For Crem alone, HL-60/AR and HL-60/Vinc cells showed markedly different responses: HL-60/Vinc cells attained intracellular DNR content comparable to HL-60/W, whereas HL-60/AR cells achieved only approximately 35% of this level. Multiple-drug effects were analyzed by calculation of the Combination Index (Chou and Talalay, Adv Enzyme Regul 22:27, 1984), which indicated that CsA and Crem are synergistic in causing enhancement of DNR accumulation in these MDR HL-60 cell lines. In blasts from AML patients, 5 mumol/L CsA/Crem or an equivalent amount of Crem alone each caused significant (P < .001) enhancement of DNR accumulation (60 AML-patient marrow samples) or DNR retention (51 AML-patient marrows). Similarly, CsA/Crem or Crem alone caused significant (P < .01) enhancement of the cytotoxicity of DNR in 36 AML blast cell specimens. The degree of enhancement of accumulation/retention or cytotoxicity by CsA/Crem was approximately equivalent to that obtained with Crem alone. These studies indicate that Crem can reverse an MDR phenotype in patient AML blast cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Survival↗
PubMed1994

Characterization of the gene encoding dihydroflavonol 4-reductase in tomato.

A cDNA clone (DFR) encoding dihydroflavonol 4-reductase was identified from tomato hypocotyls. Nucleotide and amino acid sequence comparisons to Petunia hybrida, Antirrhinum majus and Zea mays DFR sequences confirmed that the cDNA encodes the structural DFR gene. In tomato, the DFR sequence appeared to be present as a single gene and mapped to a region on chromosome 2 near two loci affecting anthocyanin pigmentation, are and aw. DFR was expressed in both leaf and hypocotyl tissue. Sequencing data from two DFR cDNA clones indicated there are alternative polyadenylation sites on DFR.

Alcohol Oxidoreductases↗
PubMed1994

Localization of diazepam-binding inhibitor and peripheral type benzodiazepine binding sites in the rat ovary.

Diazepam-binding inhibitor (DBI) is the precursor of a family of peptides, including an octadecaneuropeptide (ODN), that share with DBI the ability to specifically displace benzodiazepines (BZD) from their receptors. An association of ODN with the peripheral type BZD receptors (PBR) has been reported in the brain and a few peripheral tissues. In order to investigate whether DBI and PBR are present in ovarian tissue, we have localized DBI by means of immunocytochemistry, in situ hybridization and autoradiography of PBR in the rat ovary. Immunocytochemical localization was achieved by means of rabbit antibodies developed against rat ODN. Immunostaining was located in the cytoplasm of the theca interna, corpus luteum and interstitial gland cells, but not in the granulosa cells. Hybridization signal obtained following in situ hybridization with a [35S]-labelled single-stranded RNA probe complementary to DBI mRNA was observed in all the steroid-secreting cells, including granulosa cells of developing and mature follicles. Autoradiographic localization of PBR obtained by incubating ovary sections with [3H] PK11195, a ligand selective for PBR, revealed the presence of specific labelling in all the steroid-secreting cells. These results, which demonstrate for the first time that the ovarian steroid-secreting cells contain both PBR and its endogenous ligand, suggest that the BZD receptor might be involved in the regulation of ovarian function.

Animals↗
PubMed1994

The value of duplex scanning in surveillance of infra-inguinal vein and synthetic grafts.

The contribution of duplex scanning to improving early diagnosis of graft stenosis was evaluated in 195 patients after infrainguinal bypass procedures. Over a 31 month period. 406 duplex scans were obtained on 232 limbs with 191 vein and 41 polytetrafluoroethylene (PTFE) grafts. Peak systolic velocities > 200 cm/s with spectral broadening and lumen reduction on B-mode image were the criteria adopted for identification of a haemodynamically significant (> 50%) stenosis. Sixty-one stenoses were identified in 55 of the grafted limbs. Thirty-three of the 55 limbs had a subsequent angiogram. The angiogram showed graft occlusion in six limbs, graft stenosis in 18, and native artery stenosis in four. Twenty-one of the grafts had the angiogram within 1 month after the duplex had detected graft stenosis, and one (4.76%) became occluded in this interval. Seven had an angiogram more than 1 month after the duplex study, and five (71.4%) had become occluded. The angiographic study did not confirm a graft stenosis in five limbs. Three were submitted to operation and stenosis was confirmed. Seventeen graft thromboses were detected by duplex scanning. Graft thrombosis was demonstrated following a previous negative duplex scan in one of the 106 vein grafts (0.94%), and in four of 30 PTFE grafts (13.3%). Duplex scanning is effective in the detection of graft stenosis. The precise anatomical location is less accurate when in the region of an anastomosis. Early attention should be taken when duplex studies suggest critical stenosis because there is a high risk of occlusion. Polytetrafluoroethylene grafts tend to thrombose without a precursory focal stenosis.

Aftercare↗
PubMed1994

An anatomic source of false venous reflux with continuous wave Doppler.

BACKGROUND: The limitations of continuous wave (CW) Doppler have been recognized in the assessment of venous reflux since CW Doppler is not able to distinguish reflux signals from more than one vein. In our experience, some regions with venous reflux suggested by CW Doppler were noted to have no reflux in any individual vein during duplex studies. OBJECTIVE: The aim of the study was to assess the anatomic source of the venous reflux suggested by CW Doppler but not confirmed by duplex ultrasound. METHODS: Five hundred and fifty-one consecutive lower limbs with primary or recurrent varicose veins were examined with CW Doppler and subsequently by color-coded duplex ultrasound to assess the source of venous reflux. RESULTS: The duplex ultrasound study revealed no reflux in 44 specific regions (8%) where reflux had been indicated by CW Doppler. Two types of anatomy were noted. Two or more superficial veins joined the deep venous system via a common junction in 25 cases. A descending vein joined the deep venous system in 19 cases. CONCLUSION: A bidirectional Doppler signal in a region of venous junction without any incompetent veins can be misinterpreted as venous reflux. A careful examination of veins not only at the region of the junction, but also at some distance down the stem of the vein is important during CW Doppler or duplex assessment.

Femoral Vein↗
PubMed1994

Transfection of a nonactive site mutant murine DHFR cDNA (the tryptophan 15 mutant) into Chinese hamster ovary and mouse marrow progenitor cells imparts MTX resistance in vitro.

Chinese hamster ovary (CHO) DHFR-cells were converted to the DHFR+ (dihydrofolate reductase) phenotype when transfected with a mammalian expression vector containing the murine mutant Trp15 DHFR cDNA. Transfection of the Trp15 DHFR cDNA into wild-type CHO cells resulted in resistance to high levels of methotrexate (MTX) in vitro indicating that this mutant DHFR cDNA can act as a dominant marker. Southern and Northern blot analyses of transfected cells indicated that the transfected mutant DHFR cDNA was integrated and expressed. Gene copy number analysis showed that the Trp15 cDNA was amplifiable in increasing concentrations of MTX. Transfection of murine bone marrow progenitor cells with the Trp15 mutant DHFR cDNA resulted in MTX resistant colony forming units-granulocyte macrophage.

Animals↗
PubMed1994

The mitochondrial DNA mutation at position 11778 in Chinese families with Leber's hereditary optic neuropathy.

We amplified the 340 bp of mitochondrial DNA (mtDNA) by PCR including the recognized sequence of restriction enzyme of SfaN I. After amplification and digestion of SfaN I, two bands of 190 bp and 150 bp appeared in the mtDNA of four normal individuals but only one band of 340 bp appeared in the mtDNA with the mutation of G to A at the site of the nucleotide 11778 because such mutation destroyed the recognized sequence of SfaN I. We studied the mtDNAs of the patients with Leber's hereditary optic neuropathy from 19 Chinese families and their maternal relatives as well as the normal individuals i. e. the husbands of the female members of the pedigrees. The results show that 66.7% of the patients (30/45) and 54.7% of the maternal relatives (29/53) have such a mutation, while no such a mutation exists in the four normal individuals. So, we conclude that the mutation of mitochondrial DNA at position 11,778 is also a major cause of LHON in China.

Asian People↗
PubMed1994

Percutaneous transluminal angioplasty: follow-up with treadmill exercise testing.

Between 1986 and 1992, 308 percutaneous transluminal angioplasties in 252 patients were reviewed in the vascular laboratory of the Austin Hospital. The follow-up period ranged from 1 month to 6 years. Treadmill exercise testing was used as an additional mode of assessment to resting ankle/brachial pressure indices in monitoring outcome. Early haemodynamic improvement rate was 86.7%. In 267 successful cases, 199 had increased the mean(s.d.) resting ankle/brachial pressure index from 0.68(0.15) to 0.96(0.14) (P < 0.05) and another 68 with normal or unchanged resting ankle/brachial pressure indices after the procedure increased the mean(s.d.) post-exercise pressure index from 0.45(0.24) to 0.82(0.23) (P < 0.05). The primary haemodynamic improvement rate of initially successful percutaneous transluminal angioplasties was 80.1% at 1 year and was maintained in 46.1% of cases 5 years after. Treadmill exercise testing revealed reduction of the ankle/brachial pressure index in 69 patients during follow-up, indicating restenosis of the dilated lesion or development of a new arterial stenosis. Fifty-two of the 69 patients exhibited a significant drop in the resting pressure index. However, in the 17 remaining patients, only the post-exercise index decrease indicated haemodynamic deterioration. Treadmill exercise testing proved to be valuable adjunct in detecting haemodynamic changes after percutaneous transluminal angioplasty.

Adult↗
PubMed1993

Altered messenger RNA and unique mutational profiles of p53 and Rb in human esophageal carcinomas.

Seventy-nine esophageal carcinoma patients were studied for genetic abnormalities in the p53 and Rb tumor suppressor genes. Single-strand conformation polymorphism analysis and DNA sequencing were used to detect p53 point mutations, Northern blotting was used to examine abnormal expression of p53 and Rb, and polymerase chain reaction and Southern blotting were used to analyze allelic loss. Twenty-five cases were analyzed by DNA sequencing to detect mutations in p53. Fourteen samples contained mutations within exons 5 through 9 of p53; seven had missense mutations giving rise to single amino acid substitutions. The remaining seven (50%) contained nonsense mutations leading to premature termination, five due to single base pair substitutions, and two that were the result of frameshift mutations. In other human tumors, p53 mutations are predominantly missense mutations, but our data as well as those from other groups show that nonsense mutations are common in human esophageal cancer. All but one of the constitutionally heterozygous samples containing mutations also manifested loss of the normal p53 allele; the one exception without allelic loss contained a silent mutation, which should not have had any affect on the p53 protein product. In addition, Northern blotting analysis revealed abnormalities (altered transcript size or mRNA levels) in 5 of 7 cases involving p53 and in 2 of 7 cases analyzed for Rb. Thirty-four cases were informative for allelic loss studies of both p53 and Rb; of these, 25 (74%) lost heterozygosity of p53, Rb, or both. When point mutations and mRNA expression abnormalities were also considered, 33 of 45 (73%) tumors informative for allelic loss assays of both genes as well as for mRNA or point mutation studies showed one or more abnormalities in p53 or Rb. Our results strongly suggest that a unique profile of molecular alterations involving p53 and Rb characterizes human esophageal cancer and that these specific genetic lesions are important in the development and/or progression of most human esophageal carcinomas.

Adenocarcinoma↗