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C K Osborne

Publications and source records attributed to C K Osborne.

At least 127 records · Page 7Linked to original sources
PubMed1991

Dose intensity as a therapeutic strategy in breast cancer.

The results of systemic treatment for primary and metastatic breast cancer have plateaued in the past decade. The majority of oncologists continue to use the same chemotherapy regimens and endocrine therapies that were available in the mid 1970s. In metastatic breast cancer, still only 60-70% of patients can be expected to achieve a remission, with only 10-20% of these being a complete remission, which is usually of short duration. Metastatic breast cancer remains incurable today. Obviously, new treatment strategies are needed. The development of new active drugs, or the development of innovative ways of giving old drugs, has been disappointing in breast cancer. Similarly, combining hormones with chemotherapy, or the use of various biologic response modifiers, has not resulted in a major advance. One strategy that is currently undergoing active research is increased dose intensity of chemotherapy. This can be achieved by delivering extremely high doses of cytotoxic chemotherapy followed by hematopoietic support. A second approach involves delivering lower doses, but on a more frequent schedule than conventional programs. Preliminary results from phase II evaluation of these programs demonstrate high complete response rates, relatively short response durations, and considerable toxicity. However, 10-20% of patients treated with these regimens remain in complete remission several years after treatment, providing optimism that this approach may be effective in some patients. Advances in hematopoietic support, including autologous bone marrow transplantation (ABMT), peripheral stem cell administration, and the use of hematopoietic growth factors, have reduced toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Tamoxifen in premenopausal patients with metastatic breast cancer: a review.

The antiestrogen tamoxifen is the most widely used hormonal therapy for breast cancer. The drug exerts its antiproliferative effects primarily through estrogen receptor (ER)-mediated mechanisms, although other cellular actions may augment tumor inhibition. Clinically, tamoxifen has been less well studied in premenopausal than in postmenopausal patients. The drug has complex endocrine effects that are dependent on the treatment duration and dose, menopausal status, and target organ. In postmenopausal women receiving tamoxifen, serum estrogen levels remain low, and the normally elevated gonadotropin levels decrease. In contrast, serum estrogen levels are strikingly elevated in many premenopausal women, and gonadotropin concentrations are either unchanged or slightly increased. Large systematic trials in metastatic breast cancer have established tamoxifen as the recommended hormonal therapy for postmenopausal women with ER-positive tumors. Tamoxifen is also an active agent for premenopausal metastatic disease, and response rates are comparable to those reported for oophorectomy. Clinical experience with tamoxifen in this younger age group, however, is more limited. Few premenopausal women (less than 400) have been included in phase II and phase III trials. Two randomized trials (total of 160 patients) comparing oophorectomy with tamoxifen do not definitively establish therapeutic equivalence, and a survival advantage for either treatment cannot be excluded. Many questions remain concerning the appropriate role for tamoxifen in premenopausal patients. Still, tamoxifen has an attractive toxicity profile, and it offers a favorable therapeutic alternative for premenopausal women with ER-positive metastatic breast cancer who wish to avoid surgical or radiation castration.

Breast Neoplasms↗
PubMed1990

Regulation of breast cancer growth by insulin-like growth factors.

The IGFs may be important autocrine, paracrine or endocrine growth factors for human breast cancer. IGF-I and II stimulate growth of cultured human breast cancer cells. IGF-I is slightly more potent, paralleling its higher affinity for the IGF-I receptor. Antibody blockade of the IGF-I receptor inhibits growth stimulation induced by both IGFs, suggesting that this receptor mediates the growth effects of both peptides. However, IGF-I receptor blockade does not inhibit estrogen (E2)-induced growth suggesting that secreted IGFs are not the major mediators of E2 action. Several breast cancer cell lines express IGF-II mRNA by both Northern analysis and RNase protection assay. IGF-II activity is found in conditioned medium by radioimmuno and radioreceptor assay, after removal of somatomedin binding proteins (BP) which are secreted in abundance. IGF-I is undetectable. BPs of congruent to 25 and 40 K predominate in ER-negative cell lines while BPs of 36 K predominate in ER-positive cells. Blockade of the IGF-I receptor inhibits anchorage-independent and monolayer growth in serum of a panel of breast cancer cell lines. Growth of one line (MDA-231) was also inhibited in vivo by receptor antibody treatment of nude mice. The antibody had no effect on growth of MCF-7 tumors. These data suggest that IGFs are important regulators of breast cancer cell proliferation and that antagonism of this pathway may offer a new treatment strategy.

Antineoplastic Agents↗
PubMed1990

Autocrine and paracrine growth regulation of breast cancer: clinical implications.

Research using experimental models of human breast cancer has broadened our understanding of the possible biochemical pathways regulating breast cancer growth. Breast cancer cells express receptors for and respond to a variety of steroid and polypeptide hormones and growth factors. Specific oncogenes are also expressed in breast cancer cells, and levels of expression may relate to tumor growth and aggressiveness. Recent studies have shown that breast cancer cells can even synthesize and secrete various growth factors that could stimulate tumor growth through autocrine and/or paracrine mechanisms. Secretion of some of these growth factors is regulated by estrogen, providing a possible mechanism for estrogen induced growth. Knowledge of these growth regulatory pathways has potentially important clinical implications. Blockade of these pathways offers new possible treatment strategies, much as antiestrogens have been used to inhibit tumor growth. Quantification of the expression of certain oncogenes, growth factor receptors, or the growth factors themselves, may provide prognostic information for the individual patient. Finally, it is plausible that measurement of these tumor products in body fluids might provide tumor markers that are useful in the diagnosis and treatment of breast cancer.

Breast Neoplasms↗
PubMed1990

Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: final results of a randomized Southwest Oncology Group study.

Cytotoxic chemotherapy has not provided survival benefit in metastatic prostate cancer, although it has been used most frequently in patients with far-advanced, refractory disease. To evaluate the effects of chemotherapy given earlier in the course of the disease, the Southwest Oncology Group (SWOG) performed a randomized trial between September 1982 and October 1986 comparing endocrine therapy (diethylstilbestrol [DES] or orchiectomy) alone followed by cyclophosphamide-Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) chemotherapy at progression versus initial combined chemo-endocrine therapy. One hundred forty-three patients were registered, and only six were declared ineligible. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63%) compared with endocrine therapy alone (48%). A log-linear model of tumor response and treatment arm adjusted for the stratification factors favored the combination arm (P = .059). Only three of 27 patients on the endocrine therapy alone arm had an objective partial response when crossed over to chemotherapy, while two others had stable disease. Despite the difference in initial response rate, time to treatment failure and survival were identical in the two treatment arms. Seventy-seven percent of patients on the initial endocrine therapy alone arm have died (median survival, 25.6 months) compared with 78% on the chemo-endocrine therapy arm (median survival, 22.0 months). No significant effect of treatment on survival was observed even after adjustment for the stratification variables in a Cox regression model. Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy. Eighty-six percent of patients treated by orchiectomy have died compared with only 65% of those treated with DES. These data do not support the addition of cytotoxic chemotherapy to initial endocrine therapy in patients with metastatic prostate cancer.

Adult↗
PubMed1990

Insulin-like growth factor binding protein secretion by breast carcinoma cell lines: correlation with estrogen receptor status.

Breast tumor cell lines have been shown to secrete several distinct polypeptide growth factors, although conflicting results exist for the insulin-like growth factors (IGFs). In contrast a limited number of breast tumor cell lines have definitely been shown to secrete the high affinity IGF binding proteins (IGFBPs) that modify IGF actions. To characterize the types of IGFBPs that are secreted by breast tumor cell lines, conditioned medium was collected from seven separate tumor cell lines, three of which were estrogen receptor (ER) negative, and four of which were ER positive. All three of the ER negative cell lines, MDA-231, MDA-330, and HS578T, secreted binding proteins of 49,000 and 43,000 Mr (IGFBP-3) as well as 29,000 (IGFBP-1) and 24,000 Mr. In contrast, all four ER positive cell lines secreted 34,000 (IGFBP-2) or 24,000 Mr forms, and none secreted the 49,000 and 43,000 or 29,000 Mr forms. BT-20, a cell line that is positive for ER messenger RNA (mRNA) but negative for ER protein, secreted predominantly a 34,000 Mr protein. The amount of total IGFBP activity released in 24 h ranged between 0.4 and 5.6 nM equivalents of IGFBP-1, and there was no significant difference between the ER positive and negative cell lines. The MCF-7 cells that produced predominantly 34,000 and 24,000 Mr forms showed a 1.8-fold increase in IGFBP secretion after estrogen stimulation. Immunoblotting and a specific RIA for IGFBP-1 showed that only the ER negative lines MDA-330, MDA-231, and HS578T secreted this form. Northern blotting analysis for the mRNA encoding this protein showed that both MDA-330 and MDA-231 contained a single 1.6 kilobase mRNA species that hybridized with an IGFBP-1 complementary DNA (cDNA) probe. Immunoblotting analysis of the other cell lines showed that only the 34,000 Mr form secreted by the ER positive cell lines reacted with IGFBP-2 antisera. Exposure of the conditioned media from the three ER negative cell lines to N-glycanase revealed that the 49,000 and 43,000 Mr forms of IGFBP were glycosylated and therefore probably represent IGFBP-3. We conclude that ER negative cell lines secrete three forms of IGFBPs, IGFBP-1, IGFBP-3, and a 24,000 Mr form. In contrast, the ER positive cell lines secrete predominantly IGFBP-2 and the 24,000 Mr form but do not secrete IGFBP-3 or 1.(ABSTRACT TRUNCATED AT 400 WORDS)

Biomarkers, Tumor↗
PubMed1989

Growth inhibition of human breast cancer cells in vitro with an antibody against the type I somatomedin receptor.

Insulin and insulin-like growth factors (IGFs) stimulate the growth of human breast cancer cells in vitro. The type I somatomedin receptor (SR), expressed in these cells, may mediate the mitogenic effects of these peptides. We have examined the effect of type I SR blockade on human breast cancer growth with a monoclonal antibody (alpha-IR3) that blocks the receptor binding domain. alpha-IR3 inhibited binding of 125I-IGF-I in all breast cancer cell lines tested. Binding affinity of alpha-IR3 was 2 to 5 times higher than that of IGF-I in MDA-231 (Kd 2.1 nM) and MCF-7 cells (Kd 0.6 nM), respectively. In the presence of 10% calf serum, the antibody inhibited anchorage-independent growth of six of seven breast cancer cell lines. This inhibition was reversible with excess IGF-I. In serum-free medium, alpha-IR3 blocked IGF-I-stimulated DNA synthesis in four of four breast cancer cell lines (MCF-7, ZR75-1, MDA-231, and HS578T). However, the antibody did not inhibit basal growth of any of the breast cancer cell lines in serum-free conditions. In three estrogen receptor-positive, estrogen-responsive breast cancer cell lines (MCF-7, ZR75-1, and T47D), type I SR blockade with alpha-IR3 failed to block estrogen-stimulated DNA synthesis or cell proliferation, indicating that secreted IGF activity is not the sole mediator of the growth effects of estrogen. In conclusion, antibody-mediated type I SR blockade does not inhibit basal growth of breast cancer cells under serum-free conditions, arguing against a critical autocrine role of endogenously secreted IGF activity in vitro. However, type I SR blockade inhibits breast cancer cell growth in the presence of serum, suggesting that serum IGFs might be critical endocrine or paracrine regulators of human breast cancer.

Antibodies, Monoclonal↗
PubMed1989

Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer. An intergroup study.

We randomly assigned 536 women who had undergone either a modified radical mastectomy or a total mastectomy with low axillary-node dissection for potentially curable breast carcinoma to receive adjuvant chemotherapy or no-treatment observation. The patients were considered at high risk for recurrence because they had either an estrogen-receptor-negative tumor of any size or an estrogen-receptor-positive tumor at least 3 cm in diameter with no histopathological evidence of axillary-node involvement. The chemotherapy consisted of six four-week cycles of cyclophosphamide (100 mg per square meter of body-surface area orally on days 1 through 14), methotrexate (40 mg per square meter intravenously on days 1 and 8), fluorouracil (600 mg per square meter intravenously on days 1 and 8), and prednisone (40 mg per square meter orally on days 1 through 14). Treatments were balanced with respect to patients' characteristics. The analysis included 406 eligible patients who were entered in the study before October 1, 1987. The overall disease-free survival among patients treated with the four-drug regimen was 84 percent, as compared with 69 percent for the control group, at a median follow-up of three years (P = 0.0001). A treatment benefit was also observed in premenopausal and postmenopausal patients as well as in patients with estrogen-receptor-positive or with estrogen-receptor-negative tumors. Severe or life-threatening hematologic toxicity was encountered in 33 percent of the treated patients, with one death. Our results indicate that adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, fluorouracil, and prednisone is effective in improving three-year disease-free survival among high-risk patients with axillary-node-negative, operable breast cancer. An analysis of the effect of treatment on survival awaits a longer follow-up.

Adult↗
PubMed1989

Antitumor activity and murine pharmacokinetics of parenteral acronycine.

The lipophilic antitumor alkaloid acronycine (ACRO) was solubilized in the cosolvent system used for etoposide. ACRO in this etoposide diluent (VPD) was found to be cytotoxic (less than or equal to 50% colony formation in soft agar) in fresh human tumors from patients with renal cell cancer, ovarian cancer, uterine cancer, and metastatic tumors of unknown primary. In P-glycoprotein-positive, multidrug-resistant (MDR) cell lines, ACRO in VPD was active in MDR Chinese hamster ovary cells but not against MDR L1210 murine leukemia cells, 8226 human myeloma cells, or human CCRF-CEM lymphoblasts. In mice, ACRO in VPD was active in two solid tumor models and an i.p. MOPC-315 plasmacytoma model. ACRO i.p. in 10% VPD (v/v%) produced significant tumor growth delays in (a) nude mice bearing human MCF-7 breast cancer xenografts and (b) C57BL mice bearing colon 38 tumor. In MOPC-315-bearing mice, a single i.p. ACRO dose of 25 mg/kg was as effective as melphalan (15 mg/kg) at prolonging life span. Finally, ACRO pharmacokinetics was evaluated in mice given single 25-mg/kg doses i.p. or p.o. The oral bioavailability of an ACRO solution in VPD was only 50% but both i.p. and p.o. regimens achieved plasma levels greater than 1.0 micrograms/ml. The plasma half-life was just under 2 h. These results show that parenteral ACRO in VPD comprises a cytotoxic antitumor agent with improved bioavailability over p.o. administration. ACRO is active in vitro against several human solid tumors but is cross-resistant in 3 of 4 MDR tumor cell lines. The prior clinical activity of p.o. ACRO in myeloma and the new results in MOPC-315 plasmacytomas in mice suggest that ACRO in VPD could have activity against human multiple myeloma.

Acronine↗
PubMed1989

Phase II trial of a new biological response modifier (ImuVert) in advanced prostate cancer.

ImuVert, a new biological response modifier of bacterial origin, was evaluated in a Phase II trial of patients with metastatic prostate cancer. Sixteen patients with hormone refractory measurable or evaluable disease were treated with ImuVert 1.0 mg subcutaneously once weekly for 5 weeks. After a 1 week rest period, the dose was escalated to 3.0 mg weekly for 5 additional weeks. Eleven patients received the full 10 weeks of therapy. Toxicity consisted of mild transient flu-like symptoms as well as the development of tenderness and induration at injection sites. No patient responded to treatment. ImuVert at this dose and schedule is inactive in advanced prostate cancer.

Aged↗
PubMed1989

Tumor and serum tamoxifen concentrations in the athymic nude mouse.

The athymic nude mouse has been used as an in vivo model for pharmacologic studies of the antiestrogen, tamoxifen. Serum and tumor tamoxifen and metabolite concentrations were examined during and after 100 and 1000 micrograms/day doses injected s.c. Tamoxifen and tamoxifen metabolites were quantitated by high-performance liquid chromatography. Tamoxifen was detected in tumors after a dose of 100 micrograms/day, although serum concentrations were not detected. At a dose of 1000 micrograms/day, tumor tamoxifen and its active metabolites were detected in high concentrations ranging up to greater than 6 mmol/g tissue. Serum tamoxifen metabolites were not detected at either dose. In summary, high doses of tamoxifen were required in the nude mouse to obtain clinically relevant serum concentrations, and significant tumor levels were achieved at doses that resulted in undetectable serum levels. The relationship between serum tamoxifen concentrations, tumor tamoxifen levels, and the biologic activity of the drug requires further study.

Animals↗
PubMed1989

Megestrol acetate in breast cancer--a panel discussion.

Physicians have been using hormonal manipulation to treat advanced breast cancer for almost a century. Surgical ablation of the ovaries, adrenals, and pituitary glands has achieved remarkable tumor regression in sensitive patients. Alternatively, large doses of estrogens, progestins, and androgens have achieved similar results. More recently, the emergence of new therapies, such as antiestrogens, LHRH agonists, and chemical blockade of adrenal steroid biosynthesis offer additional choices. Within limits, all of these therapies are equally effective in sensitive patients. The trend at the present time is to select a therapy that will produce a good response with minimal toxicity. Here the participating physicians will discuss one such therapy-Megace (megestrol acetate). They will consider the role of Megace in the treatment of advanced breast cancer along with issues such as toxicity, dose response, etc.

Breast Neoplasms↗