Biomedical subjects

G W Sledge

Publications and source records attributed to G W Sledge.

At least 73 records · Page 4Linked to original sources

PubMed1996

Relationship between platinum-DNA adducts in leukocytes of patients with advanced germ cell cancer and survival.

Platinum-DNA adducts can be measured in peripheral blood leukocytes during platinum-based chemotherapy, and high adduct levels have been correlated with favorable clinical response in patients with germ cell cancer. Twenty-five patients with advanced germ cell cancer were treated with platinum-based chemotherapy regimens using the same dose and schedule of cisplatin. Platinum-DNA adducts were measured by atomic absorption spectrometry on the first and fifth days of the first cycle of cisplatin-based therapy. The patients were followed prospectively for 6-35 months (median, 26 months). Twenty-two patients had adduct levels measured 24 h after the first dose of cisplatin. There was no difference in the mean adduct levels of those who were alive and without progression of disease compared to those who were dead or progressing (P = 0.65). Twenty-three patients had day 5 adduct levels measured. The mean day 5 adduct level in the 15 patients who were alive and without progression was 62.133 fmol/microgram compared to 153.50 fmol/microgram in the patients who were dead or progressing (two-sided P = 0.02). Contrary to previous reports, these data indicate that high platinum-DNA adduct levels do not correlate with favorable outcome in patients with advanced germ cell cancer.

Adolescent↗

PubMed1995

Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice.

BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the invasion and metastasis of human cancers by mediating the degradation of extracellular matrix components. Therefore, these enzymes constitute promising targets in the development of anticancer therapies. Batimastat ([(4-N-hydroxyamino)-2R-isobutyl-3S-(thienyl-thiomethyl)succinyl]-L- phenyl-alanine-N-methylamide) is one of a new class of agents designed to inhibit MMP activity. PURPOSE: We asked whether batimastat, given as adjuvant therapy after primary tumor resection, could inhibit local-regional tumor regrowth and the formation of lung metastases in a human breast cancer xenograft model. We also explored possible effects of batimastat on breast cancer cell viability and on the accumulation of specific messenger RNAs (mRNAs). METHODS: Human MDA-MB-435 breast cancer cells were treated in vitro for 6 days with batimastat at concentrations ranging from 0.1 to 10.0 microM, and then viable cell counts were performed. The activity of collagenases, directly associated with cultured MDA-MB-435 cells or released into their culture fluids, was assessed by gelatin zymography after 1 and 3 days of batimastat treatment (drug range, 0.2-2.0 microM). Athymic nude mice were given daily intraperitoneal injections of batimastat (30 mg/kg body weight) after resection of MDA-MB-435 primary tumors grown in their mammary fat pads; the volumes of tumor regrowths and the numbers and volumes of lung metastases were calculated; neovascularization in the regrowths was assessed by immunohistochemical analysis with an antibody directed against CD31, an endothelial cell antigen. The effect of batimastat treatment on the accumulation of mRNAs encoding specific MMPs and the tissue inhibitor of metalloproteinases-2 (TIMP-2) in cultured cells, primary tumors, and tumor regrowths was measured by RNA dot blotting and hybridization with complementary probes. Linear regression analysis, Student's t tests, and chi-squared analysis were used to evaluate the data. RESULTS: The viability of cultured MDA-MB-435 cells was not affected by treatment with batimastat; however, measured activities for the 72-kd and 92-kd collagenases released by these cells were reduced after batimastat treatment. Intraperitoneal injection of batimastat significantly inhibited the local-regional regrowth of resected MDA-MB-435 tumors in athymic nude mice (in comparison with control mice, P = .035), and it reduced the incidence (P < .05), number (P = .0001), and total volume (P = .0001) of lung metastases. Batimastat treatment did not affect cellular levels of MMP or TIMP-2 mRNAs. CONCLUSION: Batimastat inhibits human breast cancer regrowth and metastasis in a nude mouse xenograft model. Potential mechanisms for batimastat's inhibitory activity do not include direct cell toxicity or alteration of MMP or TIMP mRNA levels.

Animals↗

PubMed1995

Quercetin down-regulates signal transduction in human breast carcinoma cells.

Signal transduction activity was markedly elevated in cancer cells as shown by the increased activity of enzymes utilizing 1-phosphatidylinositol, PI (PI 4-kinase and PI-4-phosphate 5-kinase) for the production of the second messenger inositol 1,4,5-trisphosphate, IP3, in rat hepatomas (Cancer Res. 54: 2611;5574, 1994) and in human ovarian and breast carcinoma cells (Life Sci. 55:1487, 1994). Quercetin, a flavonoid, in human breast carcinoma MDA-MB-435 cells produced growth inhibition (IC50 = 55 microM) and cytotoxicity (LC50 = 26 microM). Quercetin inhibited PI kinase activity in extracts of breast carcinoma cells (IC50 = 6 microM) and in cultured cells (IC50 = 10 microM) with a minor inhibition of PIP kinase activity. IP3 concentration decreased in parallel with PI kinase activity. In time sequence studies quercetin in breast carcinoma cells brought down PI kinase and IP3 concentration in 60 min to 5 and 6%, respectively; PIP kinase activity was at 63% of controls. The results demonstrate for the first time in proliferating human breast carcinoma cells a reduction by quercetin of the increased capacity for signal transduction, thus providing a novel and sensitive target in cancer cells.

1-Phosphatidylinositol 4-Kinase↗

PubMed1995

Regulation of signal transduction.

1. A systematic study is reported on the control of 1-phosphatidylinositol 4-kinase (PI kinase) and PI 4-phosphate 5-kinase (PIP kinase), enzymes of the phosphatidylinositol phosphorylation pathway which leads to the production of second messengers. IP3 and DAG. In liver of normal male, adult, fed Wistar rats the steady state activity of PI kinase was 0.5 +/- 0.01 and that of PIP kinase was 0.046 +/- 0.003 nmol/hr/mg protein. The concentration of IP3 was 1.8 +/- 0.1 pmol/mg protein. 2. That the two kinases have short half-lives was observed in starvation. where in the rat liver or bone marrow activities rapidly decreased and on refeeding were restored in a day. Injection to rats of the protein synthetic inhibitor, cycloheximide, yielded t1/2 = 80 min for the two enzymes in bone marrow and t1/2 = 80 min in liver. 3. Linkage of the signal transduction enzymes with proliferation was shown by the high activities as compared to liver of these enzymes in rat organs of high cell renewal capacity, e.g., thymus, bone marrow, spleen and testes. 4. Linkage with malignant proliferation was indicated by the observation that in rat hepatomas the enzyme activities increased 5- to 9-fold and were highest in rapidly growing hepatoma 3924A (29- and 45-fold). 5. In human primary ovarian carcinoma PI and PIP kinase activities were elevated 4.4 and 2.9-fold, respectively, and in OVCAR-5 cells, 32- and 11-fold, respectively. Similar increases were observed in MDA-MB-435 human breast carcinoma cells in comparison with normal breast parenchymal cells. 6. The linkage of signal transduction enzyme activities with malignant proliferation was also observed in experiments when human breast carcinoma cells were plated in flasks and expressed their proliferative capacity in the log phase. PI and PIP kinase activities steadily and coordinately increased to a peak 11-fold rise in mid-log phase. In late log and plateau phases the kinase activities gradually declined to the starting level. Similar observations were made for the two enzymes in human ovarian carcinoma OVCAR-5 cells and in rat hepatoma 3924A cells in tissue culture. 7. In animals injected with cycloheximide the bone marrow PI and PIP kinase activities exhibited t1/2 = 0.12 hr, the shortest decay rate in comparison with 8 enzymes of purine and pyrimidine biosynthesis with t1/2 = 0.6 to 4.3 hr. 8. Injection of tiazofurin decreased PI and PIP kinase activities in the bone marrow with t1/2 = 82 and 78 min, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Phosphatidylinositol 4-Kinase↗

PubMed1995

Tandem autotransplantation for the treatment of metastatic breast cancer.

PURPOSE: To investigate the tolerability and impact on progression-free and overall survival of two consecutive cycles of high-dose chemotherapy (HDC) with autologous bone marrow transplantation (ABMT) in patients with previously untreated metastatic breast cancer. PATIENTS AND METHODS: Twenty-eight patients received conventional-dose induction therapy (ITx) followed by a planned two cycles of HDC with ABMT. Median age was 45 years (range, 34 to 60 years). Sites of disease were bone (seven patients), visceral (three), soft tissue (11), multiple (six), and CNS (one). The ITx regimens of cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), methotrexate, fluorouracil, prednisone, and tamoxifen (CAMFTP) (three patients); fluorouracil, doxorubicin, and cyclophosphamide (FAC; 11 patients); cyclophosphamide, methotrexate, and fluorouracil (CMF; four patients); or doxorubicin or mitoxantrone/cyclophosphamide (10 patients) were given to maximum response (three to five cycles). HDC was cyclophosphamide 6 g/m2, carboplatin 2 g/m2, and etoposide 625 mg/m2 with ABMT. RESULTS: Of 28 patients, 24 received two (86%) cycles of HDC. Four received only one cycle due to persistent toxicity from course 1 (one patient), no response to course 1 (two), and death on course 1 (one). Grade 3 to 4 nonhematologic toxicities included mucositis (in one or both cycles in 21 of 28 patients; 75%), diarrhea, nausea, and vomiting. Reversible peripheral neuropathy was seen in 15 of 28 patients and was severe in one. Documented infections were seen in 19 of 52 cycles. There was one transplant-related death. Six patients were converted from partial remission (PR) to complete remission (CR) with HDC; two of 24 patients (8%) were converted from PR to CR with the second cycle of HDC. Progression-free survival rate is nine of 28 patients (32%) with median follow-up of 23 months (range, 13 to 36+ months). Eighteen of 28 patients (64%) have progressed at 1 to 17 months from ABMT. CONCLUSION: Two cycles of HDC with ABMT was well tolerated with a high response rate in patients with metastatic breast cancer. The importance of the second cycle of HDC in this population is unclear.

Adult↗

PubMed1995

Doxorubicin/paclitaxel combination chemotherapy for metastatic breast cancer: the Eastern Cooperative Oncology Group experience.

The addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to the therapeutic armamentarium for breast cancer has resulted in novel opportunities and challenges for the clinician. In a series of trials that began in 1992, the Eastern Cooperative Oncology Group (ECOG) investigated the role of paclitaxel in combination with doxorubicin for the treatment of patients with advanced breast cancer. The design of the first trial, a limited-institution pilot study, involved alternating doxorubicin and paclitaxel as single agents. The alternating schedule was well tolerated and associated with objective responses in seven of 12 patients entered into the trial. In the second trial, a limited-institution phase I trial, bolus doxorubicin was combined with paclitaxel administered over a 24-hour infusion, with administration of the two drugs separated by 4 hours. While no dose-limiting toxicity was seen at doses of 50 and 150 mg/m2 of doxorubicin and paclitaxel, respectively, dose-limiting mucositis occurred at respective doses of 60 and 175 mg/m2. Mucositis was more common when administration of paclitaxel preceded that of doxorubicin than when doxorubicin preceded paclitaxel. Based on these results, the ECOG initiated a phase III trial comparing single-agent paclitaxel, single-agent doxorubicin, and the combination of paclitaxel and doxorubicin. This study, now an Intergroup trial of ECOG, the Southwest Oncology Group, and the North Central Cancer Treatment Group, is designed to accrue 730 patients. This trial will close to accrual in September 1995, and analysis of the trial should provide useful information regarding the potential synergy of doxorubicin and paclitaxel, the degree of cross-resistance between the two compounds, and the relationship between steady-state paclitaxel levels and response to therapy. In addition, ECOG is currently conducting a trial designed to confirm the striking activity of cisplatin and paclitaxel seen in the British Columbia trials. Future trials by the group will examine means of combining paclitaxel with other active agents.

Antibiotics, Antineoplastic↗

PubMed1995

Eastern Cooperative Oncology Group studies of paclitaxel and doxorubicin in advanced breast cancer.

Based on their single-agent activity in metastatic breast cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and doxorubicin have been alternated and combined in Eastern Cooperative Oncology Group studies to identify a tolerable dose and schedule. A pilot trial in patients who had received no more than one prior chemotherapy regimen alternated paclitaxel 200 mg/m2 and doxorubicin 75 mg/m2 every 3 weeks. Seven of 12 patients had objective (complete plus partial) responses. A second (phase I) trial combined doxorubicin as an intravenous push and paclitaxel as a 24-hour continuous infusion. To evaluate the effect of the schedule on toxicity, the drug administration sequence (doxorubicin-->paclitaxel or paclitaxel-->doxorubicin) was alternated both between and within patients. initial doses were paclitaxel 150 mg/m2 and doxorubicin 50 mg/m2 in six patients, with a subsequent six patients receiving 175 and 60 mg/m2, respectively. Dose-limiting mucositis was seen at the second dose level when paclitaxel preceded doxorubicin, suggesting an important role for the administration sequence in determining toxicity (and possibly efficacy) in this regimen. These results support the sequence of doxorubicin 50 mg/m2 followed by paclitaxel 150 mg/m2 as the maximum tolerated dose. This combination has been incorporated as a treatment arm in an ongoing randomized prospective phase III Intergroup trial. By comparing the combination with both drugs as single agents (with crossover to the opposite agent at disease progression), investigators will attempt to assess response, toxicity, and time to progression as well as the degree of cross-resistance between the two agents. Given the poor prognosis of patients with advanced breast cancer, the three arms also will be evaluated in terms of patients' quality of life.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Effects of doxycycline on in vitro growth, migration, and gelatinase activity of breast carcinoma cells.

Metastatic disease is one of the major causes of death from cancer in human beings. Several enzyme systems have been implicated in the metastatic process, but the metalloproteinases (MPs) appear to be the major group involved in most instances of neoplastic invasion. Increased MP activity has been correlated with the metastatic potential of many cancers, including breast cancer. MPs also play a role in tumor angiogenesis. Tetracyclines are antimicrobial agents that can suppress MP activity in a variety of tissues, including gingiva, bone, and cartilage. Several reports have indicated that tetracyclines can suppress tumor MPs as well. A synthetic tetracycline, doxycycline, inhibits migration of human MDA-MB-435 breast adenocarcinoma cells through a reconstituted basement membrane (Matrigel), an assay used as an in vitro surrogate for the in vivo process of tumor invasion through basement membranes. Additionally, doxycycline diminishes the proliferation of this breast cancer cell line and also decreases its gelatinolytic activity, as determined by gel zymography.

Adenocarcinoma↗

PubMed1994

Fertility considerations in nerve-sparing retroperitoneal lymph-node dissection.

Nerve-sparing retroperitoneal lymph-node dissection (RPLND) maintains the patient's ability to ejaculate postoperatively. However, since testicular cancer patients sometimes have diminished spermatogenesis, questions have been raised as to the advisability of nerve preservation relative to ultimate fertility. Fertility status was assessed in clinical stage A patients by two methods. These included standard semen analysis and a post-RPLND survey. The results show that approximately 75% of non-seminomatous testicular cancer patients who present in clinical stage A have fertility potential as based on semen analysis. Additionally, of those patients responding to the post-RPLND survey who had attempted pregnancy following RPLND, 76% reported attainment of pregnancy. Nerve-sparing RPLND maintains fertility potential in clinical stage I patients; furthermore, this fertility potential appears to be worth preserving as many patients will be capable of impregnating their partners.

Ejaculation↗

PubMed1994

Clonal dominance detected in metastases but not primary tumors of retrovirally marked human breast carcinoma injected into nude mice.

Human breast cancer cell lines which grow in athymic (nude) mice provide a model of tumor cell growth and metastasis. Marking transplanted tumor cell populations with retroviral vectors provides a means of studying the dynamics of tumor cell growth in vivo. We evaluated three human breast cancer cell lines, MDA-MB-435, MDA-MB-231 and MCF-7, and found the cells were highly susceptible to retroviral gene transfer after a single 2-h exposure (90.9%, 62.7% and 72.3%, respectively). MDA-MB-435 cells (5 x 10(5)) marked with a retroviral vector containing the beta-galactosidase gene (approximately 10(4) uniquely marked clones) were injected into the mammary fat pad of athymic mice to study clonal dominance. Primary tumors resected 10 weeks after injection expressed beta-galactosidase, demonstrating persistent vector expression in vivo. Southern blot analysis did not reveal clonal dominance in the primary tumors of the five mice studied. In contrast, pulmonary metastases in each animal were monoclonal or biclonal. These results demonstrate clonal dominance in pulmonary metastases but not primary tumors of retrovirally marked MDA-MB-435 cells. Our findings suggest that this model may also be used to introduce retroviral vectors expressing oncogenes, and anti-sense oncogenes, to determine their effect on tumor cell proliferation and metastasis in vivo.

Animals↗

PubMed1994

Coordinated increase in activities of the signal transduction enzymes PI kinase and PIP kinase in human cancer cells.

The steady-state activities of the first two enzymes of the phosphatidylinositol (PI) phosphorylation pathway, PI 4-kinase, EC 2.7.1.67 (PI kinase) and PI 4-phosphate 5-kinase, EC 2.7.1.68 (PIP kinase) as compared to human normal ovary are elevated in human ovarian carcinomas (4.1- and 2.7-fold) and in human OVCAR-5 cells in tissue culture (31.2- and 8.9-fold). Compared to normal human breast parenchymal cells. PI kinase and PIP kinase activities were increased in breast carcinoma MDA-MB-435 cells grown in nude mice as solid tumors (7.3- and 2.3-fold, respectively) and in MDA-MB-435 cells grown in tissue culture (95.8- and 15.5-fold, respectively). When the human carcinoma cells were plated and expressed their neoplastic proliferative program in the log phase, in the MDA-MB-435 breast carcinoma cells the PI and PIP kinase activities coordinately increased 11-fold; in ovarian carcinoma OVCAR-5 cells 5.8- and 4.5-fold, respectively. These studies provide the first evidence in human cancer cells of an increased capacity for the operation of signal transduction. This is indicated by the markedly elevated activities of PI and PIP kinases in the phosphatidylinositol phosphorylation sequence which leads to production of second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).

1-Phosphatidylinositol 4-Kinase↗

PubMed1994

Synergistic action of taxol with tiazofurin and methotrexate in human breast cancer cells: schedule-dependence.

Taxol (paclitaxel, (NSC 125973)) is an active agent in the treatment of metastatic carcinoma of the breast; however, positive responses were observed in only about 60% of cases. Therefore, drug combinations which might improve the effectiveness are required. Since tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), methotrexate (MTX) and taxol exert their anticancer action in different phases of the cell cycle and have different biochemical targets, we tested the hypothesis that tiazofurin and methotrexate might by synergistic with taxol. MDA-MB-435 human breast cancer cells were grown in monolayer in flasks. In the growth inhibition assay for tiazofurin, methotrexate and taxol the IC50s were 12.5, 0.5 and 0.016 microM, respectively, and in the clonogenic assay 4.5, 0.065 and 0.004 microM. When taxol was given 6 hr before tiazofurin, antagonism was observed and summation was seen when drugs were given simultaneously. Synergism was obtained in both growth inhibitory and clonogenic assays when tiazofurin was followed 12 hr later by taxol. Methotrexate and taxol had an antagonistic effect when they were added simultaneously or when taxol was given 6 hr before methotrexate; summation was observed when taxol was followed 12 hr later by methotrexate. Synergistic action was obtained in the clonogenic assay when methotrexate was followed 12 hr later by taxol. The protocols yielding synergism should be of value in the design of taxol-based clinical trials for breast cancer.

Cell Division↗

PubMed1994

The fertility of patients with clinical stage I testis cancer managed by nerve sparing retroperitoneal lymph node dissection.

Nerve sparing retroperitoneal lymph node dissection reliably preserves emission and ejaculation in patients with clinical stage I nonseminoma. The fertility of 51 patients who underwent nerve sparing retroperitoneal lymph node dissection was assessed by 3 different methods: standard semen analysis, analysis of chromatin content by deoxyribonucleic acid histogram and assessment of ultimate fertility status by a questionnaire. Approximately 75% of these patients have semen analyses generally considered to be in the normal range. Virtually all patients who underwent deoxyribonucleic acid histogram analysis had histograms similar to controls. A retrospective analysis of fertility was performed in 201 patients who had previously undergone nerve sparing retroperitoneal lymph node dissection. Of these patients who attempted pregnancy after nerve sparing retroperitoneal lymph node dissection 76% have been successful. Approximately 75% of patients who present with clinical stage I nonseminoma are potentially fertile. Nerve sparing retroperitoneal lymph node dissection is capable of preserving this potential in allowing these patients to father children.

Female↗

PubMed1994

A retroviral vector expressing human interferon gamma upregulates MHC antigen expression in human breast cancer and leukemia cell lines.

The use of cytokines to modify antigen expression on syngeneic murine tumor cells has led to immunization of the host from subsequent challenges with the parent tumor cell line. To determine whether this approach can be applied to human malignancies we introduced the human interferon gamma gene (IFN gamma) into the human breast cancer cell lines MDA-MB-435 and MDA-MB-231 using retroviral-mediated gene transfer. Retroviral transfer of the IFN gamma gene was associated with decreased growth, decreased tumor invasiveness, IFN gamma production, and upregulation of MHC antigens. While the MDA-MB-435 produced higher levels of IFN gamma than MDA-MB-231, MHC class I and class II antigens were upregulated in both cell lines. Introduction of this vector into the human leukemia cell line K562 led to increased expression of MHC class I antigens, but not class II. Our findings suggest that expression of interferon gamma in breast cancer cells may lead to increased recognition of breast cancer cells by the host immune system. Furthermore, these data suggest that further development of this approach to cancer immunotherapy is warranted.

Antigens, Neoplasm↗

PubMed1994

Synergism of taxol and gallium nitrate in human breast carcinoma cells: schedule dependency.

Since Taxol (paclitaxel, NSC-125973) arrests cells in mitosis and gallium nitrate (NSC-15200) inhibits cell replication in the S phase, and the two drugs have different biochemical targets, we tested the hypothesis that the combination of these drugs may be synergistic in human breast carcinoma cells. MDA-MB-435 human breast carcinoma cells were grown in monolayer in culture. Taxol and gallium inhibited cell proliferation with IC50 = 13 nM and 180 microM, respectively. In clonogenic assays, Taxol and gallium yielded IC50 = 2 nM and 25 microM, respectively. Synergism was observed in both cell proliferation and colony formation assays depending on the treatment schedule. Gallium (300 microM) 24 h prior to Taxol (10 nM) synergistically decreased cell proliferation to 6.5% of untreated cells, which was 50% of the predicted value. In clonogenic assay, gallium (40 microM) given 16 h prior to Taxol (2 nM) yielded 8.7% colony formation of the untreated cells, which was 44% of the predicted value. Combination chemotherapy with Taxol and gallium with this protocol schedule may be useful in the treatment of human breast carcinoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Paclitaxel (Taxol)/doxorubicin combinations in advanced breast cancer: the Eastern Cooperative Oncology Group experience.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to enter routine clinical practice, has aroused considerable interest due to its novel mechanism of action and its significant activity in metastatic breast cancer. Given this activity, it seemed logical to attempt to combine paclitaxel with doxorubicin, the other most active single agent in metastatic breast cancer. The Eastern Cooperative Oncology Group performed two trials investigating paclitaxel/doxorubicin combinations in patients with advanced breast cancer in an attempt to identify a tolerable dose and schedule of the combination. In the first trial, paclitaxel and doxorubicin were alternated every 3 weeks in doses of 200 mg/m2 and 75 mg/m2, respectively, for patients who had received no more than one prior chemotherapeutic regimen. Therapy was well tolerated in this setting. At these doses, paclitaxel induced more granulocytopenia and less thrombocytopenia than did doxorubicin. Objective responses (complete and partial responses) were seen in seven of 12 patients; two other patients had improved disease (relief of pain in bony metastases). A second limited-institution Eastern Cooperative Oncology Group trial evaluated paclitaxel and doxorubicin given in combination. In this phase I trial, doxorubicin was given as an intravenous push and paclitaxel as a 24-hour continuous infusion. The sequence of drug administration (D-->P or P-->D) was alternated both between and within patients, so that we might evaluate the effect of administration schedule on toxicity. Therapy was begun at an initial paclitaxel dose of 150 mg/m2 and an initial doxorubicin dose of 50 mg/m2 in six patients, with a subsequent six patients receiving 175 and 60 mg/m2, respectively, of paclitaxel and doxorubicin. In addition, patients received granulocyte colony-stimulating factor 5 micrograms/kg/d. While therapy at the initial dose level was well tolerated, dose-limiting mucositis was seen at the second dose level, although only when paclitaxel preceded doxorubicin. This suggests that sequence of drug administration in paclitaxel-based regimens may play an important role as a determinant of toxicity and (perhaps) efficacy, a finding similar to that seen when paclitaxel and cisplatin were combined in patients with ovarian cancer. Based on this study, we identified the sequence of doxorubicin (50 mg/m2) followed by paclitaxel (150 mg/m2) to be the maximum tolerated dose. This combination is currently being compared with paclitaxel alone and doxorubicin alone in patients with advanced breast cancer in an intergroup trial led by the Eastern Cooperative Oncology Group.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Unusual distribution of chromosome 12 in a testicular germ-cell tumor cell line (833K) and its cisplatin-resistant derivative (64CP9).

The distribution of chromosome 12 in a cisplatin-sensitive testicular germ-cell tumor (TGCT) cell line (833K), and its cisplatin-resistant derivative (64CP9), was studied by fluorescent in situ hybridization (FISH) using DNA alpha satellite and whole chromosome painting probes for chromosome 12. Chromosomes 12 and i(12p) in these cell lines were readily identified. However, chromosome 12-derived chromatin was also observed in acrocentric- and nonacrocentric-derived chromosomes. Several of the chromosome 12 painted regions resembled satellites and were separated from the chromosome by nonstaining stalk-like regions. In each cell line, different chromosomes were involved. In the 833K TGCT cell line these were a der(8), a der(14) with a 12-labeled "satellite" on the q arm and a der(14) with a 12-labeled "satellite" on the p arm. In the 64CP9 TGCT cell line, these were a der(5), a der(17), and a der(8). The der(8) observed in 64CP9 was different from the der(8) seen in 833K. These derived chromosomes were characterized using sequential FISH, Wright staining, and silver staining for nucleolar organizing regions (AgNORs). The non-staining stalk-like regions were AgNOR positive, indicating "ectopic" NORs. Chromosome 22 distribution in these cell lines was also studied. FISH, using a chromosome 22-specific painting probe, identified a small metacentric marker and a der(12)t(12;22) in each cell line. It is not known whether the differences in distribution of chromosome 12-derived chromatin between the two cell lines are related to cisplatin resistance. Our study shows that the distribution of chromosome 12 in the two TGCT cell lines is much more extensive than could be identified in GTG-banded karyotypes. FISH allows characterization of unidentified chromatin and thus is a valuable adjunct to traditional cytogenetic techniques.

Chromosome Banding↗

PubMed1993

Colonic adenomas in asymptomatic women with a history of breast cancer.

One hundred ninety-three asymptomatic women with a personal history of breast cancer underwent screening colonoscopy. One hundred sixty-eight women had breast cancer as their only potential risk factor for colonic neoplasia, and 25 had a family history of colorectal neoplasia in addition to their personal history of breast cancer. Among women with breast cancer, increasing age and body weight were each predictive of an increasing prevalence of colonic adenomas. The prevalence of colonic adenomas in women aged 50-75 yr whose only potential risk factor was breast cancer was 18%, and was identical to the prevalence of colonic adenomas in 186 asymptomatic average-risk control women aged 50-75 yr (odds ratio 1.0, 95% CI 0.54-1.87). We conclude that a personal history of breast cancer does not predict a higher prevalence of colonic adenomas.

Adenoma↗