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Biomedical subjects

C Wheeler

Publications and source records attributed to C Wheeler.

At least 37 records · Page 2Linked to original sources
PubMed1991

A phase I study of high-dose ifosfamide and escalating doses of carboplatin with autologous bone marrow support.

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.

Adult↗
PubMed1990

Hepatic venoocclusive disease in autologous bone marrow transplantation of solid tumors and lymphomas.

Retrospective review of 291 solid tumor and lymphoma patients undergoing autologous bone marrow transplantation (BMT) was performed to determine the influence of pretransplant characteristics and preparative regimen to the development of hepatic venoocclusive disease (VOD). Twelve patients (4.1%) developed a clinical syndrome of right upper quadrant (RUQ) tenderness or hepatomegaly, jaundice, and ascites, with or without encephalopathy, within 40 days of marrow reinfusion. Evidence of metastatic liver disease was the only pretransplant characteristic predictive for VOD (P = .0002). Sex, age, histology, hepatitis B serology, and elevated liver function tests were not predictive. No individual preparative agent had a significant effect on the development of VOD. However, a single 2-hour infusion of carmustine (BCNU) (greater than or equal to 450 mg/m2) led to an increased incidence of VOD when compared with the same dose administered in a fractionated schedule (P = .0258) when given with two other chemotherapeutic agents. Seven of eight autopsy specimens confirmed the clinical diagnosis of VOD. The four patients in whom clinical VOD resolved had lower median peak bilirubins (7.3 v 15.9 mg/dL), lower median peak creatinines (2.1 v 4.1 mg/dL), and relatively quick engraftment of neutrophils (mean, 18.7 days). One of the four patients in whom VOD resolved had other grade 4 (life-threatening) toxicities in contrast to eight of eight who succumbed. In summary, VOD is an uncommon complication in autotransplantation of solid tumors and lymphomas. Our data suggest caution in selecting patients with known metastatic liver disease and consideration of a fractionated BCNU schedule especially in combination with other alkylating agents.

Adult↗
PubMed1990

Cyclophosphamide, carmustine, and etoposide with autologous bone marrow transplantation in refractory Hodgkin's disease and non-Hodgkin's lymphoma: a dose-finding study.

Cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) is a widely used conditioning regimen in autologous bone marrow transplantation (ABMT) of patients with refractory and relapsed lymphoma. However, the maximum-tolerated dose (MTD) of these agents when used in combination has not been systematically explored. We treated 58 patients (28 with non-Hodgkin's lymphoma [NHL], 30 with Hodgkin's disease [HD]) at seven dose levels of CBV. Doses were cyclophosphamide 4,500 to 7,200 mg/m2, BCNU 450 to 600 g/m2, and VP-16 1,200 to 2,000 mg/m2. The MTD was cyclophosphamide 7,200 mg/m2, BCNU 450 mg/m2, and VP-16 2,000 mg/m2. Six hundred milligrams per square meter of BCNU was associated with five of 18 cases of interstitial pneumonitis versus two of 40 at 450 mg/m2 (P = .02). Treatment-related mortality was 5% at dose levels less than or equal to the MTD and 22% at the highest dose. In this heavily pretreated patient population, most of whom had high volume residual disease, complete responses (CRs) to CBV and ABMT occurred in 25% of assessable patients with NHL and 43% of patients with HD. Thirteen of 28 patients with NHL and 14 of 30 with HD remain free from disease progression with median follow-up of 212 and 215 days, respectively. CBV can be administered with acceptable toxicity over a wide range of doses to patients with refractory and relapsed lymphoma.

Adolescent↗
PubMed1989

Organization and structure of the Qa genes of the major histocompatibility complex of the C3H mouse: implications for Qa function and class I evolution.

We have determined the structure and organization of the entire Qa family of class I genes from the major histocompatibility complex of the C3H mouse. Restriction maps of overlapping lambda and cosmid clones reveal that there are only five Qak genes: Q1k, Q2k, Q4k, Q10k and a Q5/9 hybrid, presumably generated by unequal homologous recombination. The resulting deletion of Q6-Q9 is consistent with the Qa-2null phenotype of this mouse strain. We have sequenced the Qak genes, and predict that each may encode a class I molecule with a structure comparable with that proposed for the transplantation antigens. Furthermore, these Qa products should be able to bind peptides and interact with appropriate T-cell receptors. Interestingly, in comparing Qak and H-2k sequences, we find limited evidence of interlocus gene conversion between Qa and H-2 loci, suggesting that the Qa genes are not likely to serve as a reservoir of genetic information for the generation of H-2 diversity within this haplotype.

Amino Acid Sequence↗
PubMed1989

Repetitive ovarian response to gonadotropin stimulation in an in vitro fertilization program.

The temporal changes of estradiol levels in 19 women undergoing ovulation induction for in vitro fertilization (IVF) and embryo replacement were described by a mathematical model. The model was analyzed for differences between treatment cycles of an individual woman and between cycles of different women. This model was also used to evaluate the results of IVF treatment. The variation between cycles within individuals was found to be less than that between different women. The parameters that describe this model were found to correlate with follicular growth but not with number of oocytes retrieved, fertilized or cleaved.

Adult↗
PubMed1987

Hormonal regulation of rat uterine secretory protein synthesis.

Treatment of the rat uterus with estradiol results in many morphological and biochemical changes. In order to examine the biochemical mechanisms of these changes, we are interested in finding a protein which can be used as an end-point indicator or marker. Estradiol administration results in the increased synthesis and release of a 115,000 and 65,000 dalton protein into the incubation media. In this paper, we demonstrate that these proteins are actually subunits of a larger protein having a molecular weight of 180,000 daltons. This protein appears to be specific to the uterus and may be produced mainly or solely by the epithelial cells. In the normal estrous cycle, maximal production is seen at estrus with essentially no production at diestrus. In the immature rat, synthesis of the 180K dalton protein is blocked by the interaction of progesterone and estradiol. However, unlike some uterine responses, the 180K protein is increased by treatment with several antiestrogens. This protein is also present in sufficient quantities to allow for the production of monoclonal antibodies. Thus this protein has many attributes of an excellent "marker protein" and will be of value in future studies aimed at elucidating the molecular mechanism(s) of steroid hormone action in the uterus.

Animals↗
PubMed1987

Estrogen regulation of protein synthesis in the immature rat uterus: the effects of progesterone on proteins released into the medium during in vitro incubations.

We have previously identified two major medium proteins secreted from the rat uterus during in vitro incubations that appear to be estrogen regulated. In this study, immature rats were treated with estradiol (E2) progestins, and actinomycin D. Medium proteins were analyzed after incubation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. E2 (1 microgram) increased the synthesis of proteins with mol wt of 115,000 and 65,000. Progesterone inhibited this increase when given in doses of 500 and 250 micrograms and when given within 8 h of estradiol. Lower doses of progesterone were not completely inhibitory. When actinomycin D was given within 6 h of E2, it also inhibited the E2 stimulated increase. This system may provide a useful marker for monitoring hormonal action in the luminal epithelium and may help in understanding hormonal regulation of gene expression.

Animals↗
PubMed1987

Endometrial cytosolic and nuclear progesterone receptors in the luteal phase defect.

Basal body temperature profiles, serial serum progesterone levels, and serial endometrial biopsies were studied in 15 infertile women during 21 ovulatory cycles. Ten cycles (in 9 women) demonstrated luteal phase defects (LPD), diagnosed by a histological lag in endometrial maturation, normal luteal phase length, and normal luteal phase serum progesterone levels. Both normal and LPD cycles had a maximum amount of endometrial cytosolic progesterone receptor (PgR) on days 13-15, with a significant decline thereafter. LPD cycles had significantly lower endometrial nuclear PgR concentrations than did normal cycles during the proliferative phase, but luteal phase endometrial nuclear PgR levels were similar in both groups. In 2 LPD women treated with dydrogesterone, normal endometrial maturation and a decline in endometrial cytosolic PgR concentrations in the late luteal phase were found. Therefore, with the exception of endometrial nuclear PgR concentrations during the proliferative phase, we found no evidence for a major abnormality in endometrial PgR levels in LPD cycles with a lag in endometrial histology.

Adult↗
PubMed1987

Cervical mucus changes in relationship to urinary luteinizing hormone.

In order to evaluate the relationship between the urinary luteinizing hormone (LH) surge as detected by the OvuSTICK (Monoclonal Antibodies, Inc., Mountain View, CA) method and daily cervical mucus parameters, ten spontaneously ovulating women undergoing infertility evaluation were followed during their cycles with twice daily urinary LH testing as well as daily ultrasound, mucus evaluation, and hormonal assays of serum LH, progesterone (P), and estradiol (E2). Maximal cervical mucus scores, as determined using a modified Insler score, were noted to coincide consistently with the urinary LH surge as detected by twice daily testing and to precede ultrasound evidence of ovulation by 0 to 24 hours. Mucus scores rapidly declined in the 24-hour period following the urinary LH surge. Detection of the urinary LH surge may therefore help identify that period of time during which cervical mucus parameters are optimal and therefore facilitate the timing of artificial insemination, intercourse, or postcoital testing.

Cervix Mucus↗
PubMed1986

Prevention of anthracycline-induced cytotoxicity in hemopoietic cells by hemin.

Anthracyclines such as Adriamycin (ADR) and daunomycin markedly inhibit cell growth in vivo and in vitro. These studies demonstrate that 30 microM hemin, which induces hemoglobin synthesis in human and murine erythroleukemia cells in culture, markedly decreases the cytotoxicity of ADR in a variety of hemopoietic cell lines (K562, HEL-1, MEL-745, HL-60, and U937) and in erythroid burst-forming cells from normal human marrow. Hemin failed to protect four of the five nonhemopoietic cell lines tested, including MCF-, breast adenocarcinoma cells, C-205 colon carcinoma cells, mouse 3T3 fibroblasts, and mouse kidney VERO cells. Hemin did protect human neuroblastoma IMP-32 cells from ADR cytotoxicity; however, this nonhemopoietic cell line undergoes dendrite formation in response to hemin induction. Cytofluorographic analysis of cellular ADR content and labeling studies with [3H]daunomycin demonstrated that hemin decreases the intracellular accumulation of these anthracyclines by more than 50% in K562 erythroleukemia cells. These studies indicate that small doses of hemin prevent intracellular accumulation of anthracyclines and thereby markedly reduce anthracycline toxicity to cells. Since this protective effect is observed preferentially with hemopoietic cells, it is possible that this finding could be exploited to protect the bone marrow from the cytotoxic action of anthracyclines during therapy for nonhemopoietic tumors.

Animals↗
PubMed1985

BCG treatment of periocular sarcoid.

Twenty-six horses and five mules with periocular sarcoids were treated with intralesional injections of a purified bacillus of Calmette and Guerin (BCG) cell walls in oil suspension. All sarcoids were cured and the horses and mules remained free from recurrence of sarcoid during the two-year follow-up period.

Animals↗
PubMed1984

m-AMSA as a probe for transport phenomena associated with anthracycline resistance.

Kinetics of transport of the acridine derivative 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) were examined in P388 murine leukemia cells and in P388/ADR, a subline selected for adriamycin resistance and cross-resistant to a variety of drugs including m-AMSA. Compared with the drug-responsive parent cell line, P388/ADR cells showed impaired accumulation of m-AMSA and an enhanced rate of drug exodus. Competition studies demonstrated structural specificity of the outward transport process. There was a low degree of intracellular m-AMSA binding, and steady-state drug levels were reached in less than 1 min. These results suggest that m-AMSA will be a useful probe for studying transport systems associated with anthracycline resistance.

Aminacrine↗
PubMed1984

Hepatitis A virus: growth characteristics of in vivo and in vitro propagated wild and attenuated virus strains.

Serial passage of the MS-1 strain hepatitis A virus (HAV) in marmosets was shown to increase the yield of virus and to shorten the incubation period from approximately 55 days in the first passage to 3-7 days in the ninth and higher passages. Intravenous inoculation of susceptible chimpanzees with MS-1 HAV was found to result in a typical course of disease in two animals who had received eighth marmoset-passage virus, including the occurrence of elevated ALT activity, presence of HAV antigen in liver and stool, and seroconversion to anti-HAV. Two chimpanzees inoculated with 20th passage MS-1 HAV (M001 liver homogenate) exhibited normal or nearly normal ALT activity and had no demonstrable or significant HAV in weekly liver biopsy specimens or in serial stool suspensions obtained during 64 days of observation. However, both animals seroconverted to anti-HAV within 2 weeks after inoculation, as did the animals who had received eighth passage MS-1 HAV. These findings suggest that subpassage of the MS-1 strain of HAV in marmosets resulted in the generation of an attenuated virus strain that was still capable of inducing a vigorous antibody response in intravenously infected chimpanzees. Serial propagation of wild and attenuated strains of HAV (HAS-15 and MS-1/M001, respectively) in FRhK-4 cells was associated with a significant decrease in the growth period for both viruses. Our studies have also shown that HAS-15 HAV can be recovered in maximum yield in later passages as early as 2 to 3 days after inoculation.

Animals↗