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K Dhingra

Publications and source records attributed to K Dhingra.

At least 37 records · Page 2Linked to original sources
PubMed1996

Lipid peroxidation-induced putative malondialdehyde-DNA adducts in human breast tissues.

The etiology of the majority of human breast cancers is unknown; however, oxidative stress and lipid peroxidation have been suggested to play a role in breast carcinogenesis. To address this possibility, DNA adducts induced by malondialdehyde (MDA), an end product of lipid peroxidation, were analyzed in surgical specimens of normal breast tissues of 51 breast cancer patients using the nuclease P1-enhanced version of the 32P-postlabeling assay. Normal breast tissue samples from 28 noncancer patients receiving reduction mammoplasty served as controls. Two previously characterized putative MDA-deoxyadenosine (dA) and one MDA-deoxyguanosine adduct were detected in all tissue samples examined. Normal breast tissues from cancer patients exhibited significantly higher levels of the putative MDA adducts [median (42.5) and range (2.2-202.8) of relative adduct labeling x 10(9) values] than those found in noncancer controls (median, 15.67; range, 2.4-382.1; P = 0.0001, Mann-Whitney U test). Ten of the 51 cancer patients and 1 of the 28 controls were found to contain the putative MDA adducts at the level of > 1/10(7) nucleotides, a frequency comparable to that found in human liver. Age and body mass did not significantly influence the levels of these adducts. However, the presence of a previously detected benzo(a)pyrene-like DNA adduct in the breast tissues was associated with higher levels of the putative MDA-dA adducts in cancer patients (P = 0.012). The level of the putative MDA-dA adducts was significantly lower in smokers and former smokers compared to nonsmokers among cases after adjusting for age, body mass index, and status of the benzo(a)pyrene-like adduct (P = 0.009). Tumor tissues (n = 11) displayed significantly lower levels of the putative MDA adducts (median, 10.2; range, 5.3-20.6) than their corresponding normal adjacent tissues (median, 25.5; range, 10.5-138; P < 0.01). These findings provide evidence that lipid peroxidation products can accumulate in human breast tissues and reach relatively high levels in the breast tissues of women with breast cancer. There seems to be an interaction between these endogenous DNA modifications and carcinogen exposure-induced DNA adducts. Detection and quantitation of the putative MDA-DNA adducts may potentially be a useful tool in the understanding of breast cancer etiology.

Adult↗
PubMed1995

The effects of anaemia on heart, placenta and body weight, and blood pressure in fetal and neonatal rats.

1. Reports that maternal anaemia in pregnancy is associated with a greater placental: birth weight ratio, which predisposes towards high postnatal blood pressure in the human, led us to examine the effects of maternal anaemia during pregnancy on placental size, fetal and neonatal growth, and blood pressure development in the rat. 2. Nutritional anaemia was induced in female rats prior to mating and maintained throughout pregnancy and up until weaning of the pups. Fetuses were studied at 20 days of gestation (E20). Pups were studied on postnatal days 20 (P20) and 40 (P40), having been weaned onto normal rat chow at 21 days. 3. In the anaemic group placental: fetal body weight ratios were lower compared with controls. Body weights at all ages were lower in the anaemic group than in controls, despite a greater rate of growth in the anaemic group between P20 and P40. 4. At P20 heart weights of the anaemic group were almost twice that of controls, suggesting an alteration in their cardiovascular development. However, paradoxically, the systolic blood pressure of the anaemic group was lower than that of controls. 5. By P40 the systolic blood pressure of the anaemic group (136 +/- 3 mmHg) had increased and was greater than that in control pups (126 +/- 3 mmHg). 6. In conclusion, we have shown that there is a pronounced postnatal rise in systolic blood pressure associated with maternal anaemia during pregnancy, which is not related to a greater placental: birth weight ratio. Before weaning, anaemic pups have a lower systolic blood pressure than controls and there is an important association between the rate of postnatal growth and blood pressure.

Anemia↗
PubMed1995

Phase I clinical and pharmacological study of suppression of human antimouse antibody response to monoclonal antibody L6 by deoxyspergualin.

Development of human antimouse antibody (HAMA) is a major limiting factor in the application of murine mAb for clinical use. A novel immunomodulatory drug, deoxyspergualin (DSG), has shown potential to suppress antimouse antibody response in preclinical model systems. We conducted a Phase I trial to determine the effect of DSG on HAMA response to murine mAb L6 administered to patients with advanced cancers (in previous trials, this antibody elicited HAMA in two-thirds of the treated patients). L6 mAb was administered at a fixed dose of 200 mg/m2 on days 1-5. DSG was administered at doses of 50 mg/m2 [dose level (dl) 1] or 150 mg/m2 (dls II and III) on days 1-7. Treatment courses were repeated every 6 weeks (dls I and II) or every 3 weeks (dl III). HAMAs were quantitated by a commercially available ELISA assay (ImmuSTRIP; anti-isotypic antibodies) and a radiometric assay (antiisotypic and anti-idiotypic antibodies). Pharmacokinetics of L6 and DSG was also studied in all consenting patients. Among 24 evaluable patients, 2 patients developed detectable HAMAs using the ELISA (one each at dls I and II) after a median follow-up of 122 days (P = 0.0001 as compared to historical controls). Even in the two patients who developed HAMA, the HAMA levels were quite low (160 and 181 ng/ml; historical experience, 70-38,744 ng/ml). The radiometric assay detected anti-L6 antibodies in 13 patients (4, 6, and 3 at dls I-III, respectively) after a median of 82 days. The median highest anti-L6 antibody level was 129 ng/ml (range, 21-2150). The highest anti-L6 antibody level at dl III was only 44 ng/ml. The results suggest suppression of anti-idiotypic response also. No clinical antitumor activity was observed, and no significant changes in T4/T8 subsets or immunoglobulins occurred (suggesting a lack of generalized immunosuppression). We conclude that DSG can suppress HAMA response to L6. A starting dose of 150 mg/m2/day is recommended for Phase II trials to confirm this observation.

Adult↗
PubMed1995

Genetic changes in breast cancer--consequences for therapy?

The knowledge of specific genetic changes and their biological consequences is critical to an understanding of the natural history of breast tumors and the development of rational means to prevent and treat them. A number of genetic changes have been identified in breast tumors. Some of these involve specific genetic loci that directly contribute to one or more attributes of transformation, i.e., dysregulated proliferation and invasion, while other changes confer genetic instability that increases the possibility of acquiring subsequent, specific genetic lesions relevant to tumorigenesis. Many of these changes have been correlated with an adverse prognosis and attempts to integrate these in comprehensive multifactorial prognostic models are in progress. Initial clinical trials have also demonstrated the 'proof of concept' of targeting specific genetic lesions for therapeutic purposes. In the not too distant future, we can envision the use of specific therapies for individual (or subgroups of) tumors based on the specific genetic changes that lead to their development, rather than the global approach of multiagent cytotoxic therapy that is in widespread use today.

Breast Neoplasms↗
PubMed1995

A phase II chemoprevention trial design to identify surrogate endpoint biomarkers in breast cancer.

Surrogate biomarkers for risk assessment and efficacy of potential chemopreventive agents are needed to improve the efficiency and reduce the cost of conducting chemoprevention trials. In addition to criteria of sensitivity, specificity, quantifiability, and reproducibility applicable to most potential biomarkers, there are additional specific constraints in developing biomarkers for specific organ sites. In the case of breast tissue, these difficulties include lack of a consensus on the nature of premalignant lesions and the histologic criteria used to define them; even when such a consensus can be evolved, there are limitations in visualizing such lesions without invasive biopsies. Also, knowledge of specific genetic and biochemical changes in premalignant lesions is limited. In addition, the physiology of breast tissue is cyclic, no proven, relevant markers can be studied in a randomly obtained needle aspirate. The earliest determinate lesion that can be recognized in breast tissue is ductal carcinoma in situ (DCIS). At the University of Texas M.D. Anderson Cancer Center, we have initiated a study to develop biomarkers for tamoxifen and 4-hydroxyphenylretinamide by administering one or both of these drugs to women with DCIS or small invasive lesions in the interval between the initial diagnostic core biopsy and definitive surgery. The treatment is to be administered for 2-4 weeks. Proposed biomarkers to be studied include: (a) markers associated with neoplastic phenotypes, e.g., excessive proliferation, alternations of nuclear morphology and angiogenesis; (b) proteins likely to be required for response to the putative chemopreventive agents, e.g., estrogen receptor, nuclear retinoid receptors; (c) markers indicative of intact downstream response pathways, e.g., progesterone receptors; (d) oncogenes and tumor suppressor genes regulated by the proposed chemopreventive agents, e.g., neu, TGF-beta; and (e) potential novel markers of genetic instability that could be studied in randomly obtained needle aspirates, i.e., random chromosomal gains and losses in high risk mammary epithelium. The experience gained in designing and conducting this trial is expected to facilitate development of future chemoprevention trials of breast, as well as other organ site cancers.

Anticarcinogenic Agents↗
PubMed1995

Phase II clinical and pharmacological study of pirarubicin in combination with 5-fluorouracil and cyclophosphamide in metastatic breast cancer.

Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. We conducted a Phase II trial of an anthracycline analogue, pirarubicin, administered in combination with 5-fluorouracil and cyclophosphamide every 3 weeks, as front-line chemotherapy in women with metastatic breast cancer. Patients who had received prior anthracycline therapy were excluded. The chemotherapy doses were as follows: 5-fluorouracil (500 mg/m2 on days 1 and 8), pirarubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1). Among 40 evaluable patients treated on this protocol, a major response (partial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration was 8 months, and median survival was 16 months. Grade III/IV myelosuppression occurred in 81% of the courses. The median cumulative pirarubicin dose was 410 (range, 90-870) mg/m2. A significant decrease in left ventricular ejection fraction occurred in 12 patients (at a median cumulative pirarubicin dose of 460 mg/m2) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m2, respectively). Eleven patients underwent endomyocardial biopsy, either because they experienced a drop in left ventricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m2 and were still responding to the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a cumulative dose of 705 mg/m2). Severe alopecia occurred in two-thirds of the patients. Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, beta and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clearance of drug was 4.2 liters.1 h/kg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin. However, cardiotoxicity remains a significant problem.

Adult↗
PubMed1994

Sialyl-Tn antigen expression occurs early during human mammary carcinogenesis and is associated with high nuclear grade and aneuploidy.

Sialyl-Tn (STn) antigen represents an aberrant glycosylation product of cell surface mucin in adenocarcinomas. We studied its expression in 40 breast carcinomas (35 of which included in situ carcinomas) by performing immunostaining with B72.3 monoclonal antibody. STn expression was observed in 50% of cases and was equally frequent in in situ and in invasive carcinomas. Positive STn staining significantly correlated with high nuclear grade (P = 0.001), aneuploidy (P < 0.001) and high S-phase fraction (P = 0.02). No correlation was observed between STn staining and age, menopausal status, presence of invasive component, or hormone receptor positivity. STn staining may provide an objective marker of dedifferentiation of breast tumors and should be investigated further for its prognostic value in breast cancers and as a biomarker of malignant transformation of breast epithelium.

Adult↗
PubMed1994

Quantitative analysis of chromosome in situ hybridization signal in paraffin-embedded tissue sections.

Interphase cytogenetic analysis using chromosome-specific probes is increasingly being used to detect chromosomal aberrations on paraffin-embedded tissue sections. However, quantitative analysis of the hybridization signal is confounded by the nuclear slicing that occurs during sectioning. To determine the sensitivity and accuracy of chromosome in situ hybridization for detecting numerical chromosomal aberrations on paraffin-embedded sections, in situ hybridization was performed on sections derived from mixtures of cell populations with known frequencies of numerical chromosomal aberrations and the Chromosome Index (CI) was calculated (i.e., total number of signal spots/number of nuclei counted) as a quantitative measure of chromosome copy number. The presence of 25% or more monosomic or tetrasomic cells in a given population was easily detected as a change in CI (P < 0.05). Lower degrees of polysomy could be detected as a small percentage of nuclear fragments with > 2 signal spots. The CI was not significantly influenced by a change in section thickness from 4 to 8 microM, by an increase in cell size from 478 to 986 microM3, or by the choice of detection method (fluorescence vs. conventional bright-field microscopy). Comparative analysis of touch preparations and tissue sections from the corresponding breast tumors showed that CI accurately reflects the average copy number of chromosomes in intact nuclei and may actually be superior to in situ hybridization on whole nuclei for the detection of numerical chromosomal changes in defined histologic areas. This method is thus a sensitive and accurate means of studying genetic changes in premalignant and malignant tissue, and of assessing the genetic changes associated with specific phenotypes.

Aneuploidy↗
PubMed1994

Phase II study of deoxyspergualin in metastatic breast cancer.

We conducted a phase II trial of the novel immunomodulatory/cytotoxic agent 15-deoxyspergualin in patients with metastatic breast cancer who had failed treatment with front-line chemotherapy. Thirty-eight courses of treatment were administered to fourteen patients enrolled in this trial, 25 at a dose of 1800 mg/m2/d (dose level 0) and 13 at a dose of 2150 mg/m2/d (dose level +1) administered by continuous intravenous infusion for 5 days. Treatment was well tolerated with neuromuscular side-effects (myalgias, paresthesias) and granulocytopenia (nadir granulocyte count of 0.50-0.99 x 10(9)/l) in two and three courses, respectively, as the only grade III toxicities. The neuromuscular toxicity of deoxyspergualin is probably related to the occurrence of hypomagnesemia. No partial or complete responses were observed in this study. One patient achieved a minor response but had progressive disease 65 weeks after enrollment. The response was observed coincident with an increase in T4/T8 ratio in the peripheral blood. The median time to progression for the entire cohort was eight weeks (range, 4-65 weeks). There was no clinical evidence of immunosuppression and no decrease in total peripheral blood lymphocyte counts or helper T-cells was observed. At the doses and schedule employed in this trial, deoxyspergualin does not appear to have significant activity against metastatic breast cancer resistant to front-line chemotherapy. The correlation between hypomagnesemia and neuromuscular toxicity of deoxyspergualin is an intriguing, previously unknown observation and requires further investigation.

Adult↗
PubMed1994

Sequential Therapy in the Treatment of Locally Advanced Noninflammatory Breast Cancer.

Optimal care of patients with locally advanced breast cancer requires the use and thoughtful integration of all effective modalities of treatment. A number of alternative combinations of surgery, chemotherapy, and radiation have been promoted, each with its own particular advantages and shortcomings. The advantages of sequenced, multimodality therapy of locally advanced, noninflammatory breast cancer include (1) the ability to convert nonresectable tumors to resectable ones, (2) early institution of systemic therapy, (3) in vivo evaluation of tumor response with the potential for optimization of therapy, and (4) relatively low morbidity rates with the ability to render most patients disease-free at their primary site. The results of this treatment strategy are discussed.

Journal Article↗
PubMed1994

Effect of chromosome size on aberration levels caused by gamma radiation as detected by fluorescence in situ hybridization.

Fluorescence in situ hybridization (FISH) is a powerful technique for detecting genomic alterations at the chromosome level. To study the effect of chromosome size on aberration formation, we used FISH to detect initial damage in individual prematurely condensed chromosomes (PCC) of gamma-irradiated G0 human cells. A linear dose response for breaks and a nonlinear dose response for exchanges was obtained using a chromosome 1-specific probe. FISH detected more chromosome 1 breaks than expected from DNA based extrapolation of Giemsa stained PCC preparations. The discrepancy in the number of breaks detected by the two techniques raised questions as to whether Giemsa staining and FISH differ in their sensitivities for detecting breaks, or is chromosome 1 uniquely sensitive to gamma-radiation. To address the question of technique sensitivity, we determined total chromosome damage by FISH using a total genomic painting probe; the results obtained from Giemsa-staining and FISH were nearly identical. To determine if chromosome 1 was uniquely sensitive, we selected four different sized chromosomes for paint probes and scored them for gamma-ray induced aberrations. In these studies the number of chromosome breaks per unit DNA increased linearly with an increase in the DNA content of the chromosomes. However, the number of exchanges per unit of DNA did not increase with an increase in chromosome size. This suggests that chromosome size may influence the levels of aberrations observed. Extrapolation from measurements of a single chromosome's damage to the whole genome requires that the relative DNA content of the measured chromosome be considered.

Animals↗
PubMed1993

Strategies for the application of biomarkers for risk assessment and efficacy in breast cancer chemoprevention trials.

Current chemoprevention trial designs based on epidemiological risk assessment and occurrence of cancer as an endpoint are inefficient and expensive. Novel biomarkers are needed to facilitate the development of chemopreventive interventions. The following four categories of biomarkers may be useful in prevention trials: histologic and morphometric markers; phenotypic markers of dysregulated proliferation, differentiation, and cell loss; specific oncogenes and growth regulators which are qualitatively or quantitatively altered in breast cancers; and markers of genetic and epigenetic instability. Some of these markers will be generally useful regardless of the chemopreventive approach used, whereas others may be uniquely useful in trials of specific chemopreventive agents [e.g., upregulation of progesterone receptor (PR) expression in response to tamoxifen]. The development of these markers requires three phases of study: "Phase I": assessing the prevalence of the putative marker in malignant and premalignant tissue from individuals who have developed breast cancer; "Phase II": assessing in vivo modulation of the biomarker by the proposed chemopreventive agent; and "Phase III": applying the proposed biomarker in larger-scale trials of chemopreventive agent in high-risk populations, either before or after the development of a primary breast malignancy. The use of these biomarkers may also allow identification of novel targets for chemoprevention.

Biomarkers, Tumor↗
PubMed1993

Phase II study of alpha-interferon and 13-cis-retinoic acid in metastatic melanoma.

The combination of alpha-interferon and 13-cis-retinoic acid has shown significant activity against a number of human tumors. We conducted a phase II trial to test whether the combination would have a major response rate of 30% or more in patients with refractory, metastatic melanoma. Eleven patients were treated on the study. Alpha-interferon was administered subcutaneously three times a week at a dose of 10 million U/m2 and 13-cis-retinoic acid was administered orally at a dose of 1 mg/kg/day. No patient achieved a partial or complete remission. The combination of alpha-interferon and 13-cis-retinoic acid is unlikely to have significantly higher therapeutic activity than alpha-interferon alone.

Adult↗
PubMed1993

A phase-I clinical study of low-dose oral interferon-alpha.

Twenty-five patients with systemic malignancies or cutaneous disorders were treated with low dosages (1-16 IU/kg/day) of oral interferon-alpha in a phase-I study. There were no grade-3 or -4 toxicities. No patients achieved a partial or complete response. One patient with renal cell carcinoma had prolonged disease stabilization lasting for 22 months. No significant changes in lymphocyte subsets including T4/T8 ratio, or serum immunoglobulins were observed. Subjective improvement in general well-being was reported by three patients. Low dosages of interferon-alpha administered orally do not appear to have any significant immunomodulatory or antitumor activity.

Administration, Oral↗
PubMed1992

Chromosome in situ hybridization on formalin-fixed mammary tissue using non-isotopic, non-fluorescent probes: technical considerations and biological implications.

Fluorescent in situ hybridization techniques have provided an important tool for interphase cytogenetic studies of human neoplasms. However, these techniques are difficult to use on formalin-fixed archival tissue sections. We describe here a non-fluorescent, non-isotopic in situ hybridization (ISH) approach that is easily applicable to paraffin-embedded breast tissue sections. The technical steps that must be monitored and individualized to optimize signal generation and detection are discussed. This ISH technique has several advantages over fluorescent detection methods. The signal obtained can be viewed using an ordinary light microscope and does not fade with time. More importantly, the signal is observed and analyzed in the context of tissue morphology. The technique permits detection of numerical chromosomal abnormalities not only in malignant but also in apparently normal and potentially premalignant mammary tissue. This may allow identification of focal genetic abnormalities as well as field-defects and enable analysis of their evolution during the multistep transformation to mammary neoplasm. This technique is also suitable for analysis of tumor heterogeneity and the correlation of numerical chromosomal aberrations with histologic, immunocytochemical, and clinical features of breast tumors.

Breast↗
PubMed1992

Minimal residual disease in interferon-treated chronic myelogenous leukemia: results and pitfalls of analysis based on polymerase chain reaction.

Therapy with interferon-alpha results in complete cytogenetic remission in 15-20% of patients with chronic myelogenous leukemia. Even during prolonged clinical follow-up, most of these patients do not relapse. However, because of the limited sensitivity of cytogenetic techniques (approximately 5%) and Southern blots (approximately 1%), it is uncertain whether the residual malignant clone becomes extinct or persists below the limit of detection in these patients. We used polymerase chain reaction to amplify the chimeric BCR-ABL transcripts in 18 patients with chronic myelogenous leukemia who became Ph1 chromosome negative while receiving treatment with interferon-alpha, either alone or in combination with interferon-gamma. At the time of study, these patients had been Ph1-negative for a median of 22+ months. Fifteen patients were positive for residual BCR-ABL transcripts. No residual BCR-ABL message was detected on analysis of multiple serial samples in three patients. In order to confirm these results, the samples from these three patients, along with positive and negative controls, were analyzed by two independent laboratories in a blinded fashion. In the first laboratory, RNA specimens from all three patients were considered negative using chemiluminescent acidinium-ester-labeled probes. In the second laboratory, samples from all three patients were also negative by conventional polymerase chain reaction (PCR). However, when a second round of amplification was carried out on the amplified samples using a different combination of primers, samples from two of the three patients were positive. The results confirm the presence of a small proportion of BCR-ABL-positive cells in the majority of patients who are in complete remission and highlight some of the potential problems of PCR-based analysis. There is a need to standardize PCR methodology and potential confounding factors need to be addressed before PCR can be generally applied to analysis of minimal residual disease in CML. The implications of BCR-ABL positivity for these patients are discussed.

Adult↗
PubMed1991

Significance of the P210 versus P190 molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia.

We investigated the significance of p210 and p190 molecular abnormalities in 32 adults with Philadelphia chromosome (Ph)-positive acute leukemia. p210 was detected in 15 patients (47%), p190 in 16 (50%), and both in one (3%). p210 was noted in 11 of 24 patients (46%) with acute lymphocytic leukemia, and in four of eight patients (50%) with acute myelogenous or undifferentiated leukemia. Among 29 patients with untreated disease (p210, 14 patients; p190, 15 patients), no significant differences in the two molecularly distinct groups were observed by pretreatment characteristics including age, degree of organomegaly, anemia, leukocytosis, thrombocytopenia, occurrence of karyotypic abnormalities in addition to Ph, or residual diploid metaphases. Complete response (CR) rates were also similar. Although the remission duration tended to be longer with p190 (P = .08), the differences were minor (median duration 29 v 20 weeks) and not paralleled by differences in survival rate. In 10 patients studied by karyotypic analysis in remission, two of four patients with p190 and two of six patients with p210 showed 100% normal metaphases. One of the seven patients (14%) with p210 who achieved CR manifested a morphologic picture of second chronic-phase chronic myelogenous leukemia lasting for 1 month. We conclude that the molecular studies in Ph-positive acute leukemia are not associated with significantly different clinico-laboratory, karyotypic, or prognostic implications.

Adult↗