Dose response for adjuvant chemotherapy of breast cancer: experimental and clinical considerations.
Explore the source record for details and available documents.
Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
E Frei
Publications and source records attributed to E Frei.
Effect of lonidamine on the cytotoxicity of four alkylating agents in vitro.
We examined the ability of lonidamine, which has been described as an inhibitor of cellular respiration and glycolysis, to enhance the cytotoxicity of alkylating agents to MCF-7 human breast-carcinoma cells. Lonidamine was increasingly cytotoxic to MCF-7 cells with increasing time of exposure. With a 12-h exposure, the IC50 for lonidamine was about 365 microM, and with a 24-h exposure it was about 170 microM. A drug concentration of 250 microM was chosen for use in the drug combination studies. Lonidamine appeared to have a dose-modifying effect on cisplatin (CDDP), producing increasingly supra-additive cell kill with increasing CDDP concentration. When simultaneously incubated with lonidamine for 1 h, 500 microM CDDP yielded a cell kill that was 2 log greater than additive cytotoxicity. Extending the exposure to lonidamine for 12 h after CDDP treatment led to a small, additional aliquot of cell kill of about 2.5-fold over the CDDP concentration range. Lonidamine also appeared to have a dose-modifying effect on melphalan cytotoxicity in the melphalan concentration range of 100-500 microM. Between concentrations of 10 and 100 microM melphalan, the drug combination survival after 1 h exposure fell within the envelope of additivity for the two agents. However, maintaining the presence of lonidamine for an additional 12 h increased the effect such that the combination was supra-additive over the entire concentration range of melphalan. Simultaneous exposure to 4-hydroperoxycyclophosphamide (4-HC) and lonidamine for 1 h resulted in greater than additive cell kill, and extending the lonidamine exposure period such that lonidamine was present during and 12 h after 4-HC treatment further increased this effect. Lonidamine had a moderate effect on the cytotoxicity of carmustine (BCNU) with a 1 h simultaneous exposure; however, this treatment combination reached greater than additive cytotoxicity only at the highest concentration of BCNU tested. Extending the lonidamine exposure time for an additional 12 h resulted in supra-additive cell kill over the BCNU concentration range. Therefore, when lonidamine was present during exposure to the alkylating agent and its presence was then extended for an additional 12 h, a synergistic cell kill was produced with all four alkylating agents tested.
Alkylating Agents↗
Diverse prognosis in metastatic breast cancer: who should be offered alternative initial therapies?
In an attempt to clarify appropriate treatment options for women with stage IV breast cancer, we studied the survival experience of a large dataset of patients treated on Cancer and Leukemia Group B (CALGB) protocols. The study, restricted to women who had had no prior chemotherapy for metastatic disease, demonstrated a surprisingly poor prognosis, with an estimated median survival of 1.6 years and only 26% alive at 3 years. Analysis of prognostic factors permitted the identification of subsets with even shorter survival, such as women with estrogen receptor negative tumor in more than one metastatic site and prior adjuvant chemotherapy. We feel that an evaluation of intensive investigational treatment approaches, such as trials using autologous bone marrow transplantation, is justified for most stage IV breast cancer patients, in view of their poor prognosis.
Biomarkers, Tumor↗
Determination of intracellular reduced glutathione and glutathione related enzyme activities in cisplatin-sensitive and resistant experimental ovarian carcinoma cell lines.
The level of GSH in ovarian carcinoma cells which were sensitive and resistant to cisplatin was serially determined following tumor removal from the animals, in addition, activities of GSH-reductase and GSH-S-transferase were assessed. The GSH level in the resistant line (O-342/DDP) was almost twice as high as that in its sensitive counterpart (O-342), when determined immediately following removal of the tumor (1.55 +/- 0.47 vs. 0.81 +/- 0.32 nmol/10(6) cells). Culturing the cells resulted in a decrease of GSH levels in both cell lines during the first 4 h. Thereafter, GSH levels in both cell lines increased up to 24 h. At this time the GSH level was higher in O-342 than in O-342/DDP. GSH-reductase activity in O-342/DDP cells was significantly higher than in O-342 cells when the enzyme was determined immediately after tumor removal; at the same time there was no difference in activity of GSH-S-transferase between two cell lines. After 24 h in culture, no significant difference between O-342 and O-342/DDP cells could be observed in the activity of the two enzymes.
Animals↗
Carcinogenic properties of N-nitrodimethylamine and N-nitromethylamine in the rat.
Male and female BDVI rats were treated with 1 mmol/kg x week and 0.5 mmol/kg x week of N-nitrodimethylamine (NTDMA) or N-nitromethylamine (NTMA). NTMA induced mainly tumors of the nasal cavity (esthesioneuro-epithelioma) while NTMA induced neurinoma of the spine, spinal nerves and peripheral nerves. NTMA was slightly less potent than the dimethyl compound. Females were less susceptible than males to the carcinogenic action of the nitramines.
Administration, Oral↗
Tumor necrosis factor: still a promising agent.
Explore the source record for details and available documents.
Dose-Response Relationship, Drug↗
Bone marrow autotransplantation for solid tumors--prospects.
Autologous bone marrow transplantation (AuBMT) is in clinical trial for patients with metastatic solid tumors, particularly breast cancer. This review deals with the potential of this approach. AuBMT is curative for the leukemias and lymphomas. Curative cancer chemotherapy has, almost without exception, required combinations of agents wherein dose was well maintained. However, curative chemotherapy strategies for the hematologic neoplasms have not proven successful for the common solid tumors. An important exception is that standard adjuvant chemotherapy can "cure" some micrometastatic tumors. Preclinical studies indicate the effectiveness of alkylating agents in terms of maintained dose effect through multiple logs of tumor cell kill; difficulty in developing drug resistance; general lack of cross resistance; and synergy for alkylating agents used in combination. There is an increasingly effective experimental basis for the construct of intensification regimens employing combinations of alkylating agents. Differing nonmyelosuppressive toxicity for alkylating agents provides a basis for maintaining dose when employed in combination in the autologous marrow situation. The aforementioned studies and cytokinetic analyses of combined intensive alkylating agent therapy for breast cancer support the potential of this approach. Clinical trials indicate a high response rate in refractory breast cancer. Trials involving induction chemotherapy followed by combined alkylating agent intensification have produced substantial complete remission rates. The duration of response has, in most studies, been short. This approach is associated with major toxicity, including mortality, and is expensive. Experimental and preliminary clinical evidence as marshalled in this review indicate that this is a promising area for therapeutic research.
Antineoplastic Agents↗
A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support.
A series of 33 patients were treated with a four-day continuous infusion of carboplatin in a phase I study to determine the maximum-tolerated dose (MTD) of this agent when used with autologous bone marrow reinfusion. Doses were escalated from 375 to 2,400 mg/m2; autologous bone marrow reinfusion was added to the regimen at doses of 1,600 mg/m2 and above. The MTD was determined to be 2,000 mg/m2. Dose-limiting toxicity consisting of reversible hepatotoxicity, renal dysfunction, and moderate to severe ototoxicity was observed with a dose of 2,400 mg/m2. There were ten responses in 31 heavily pretreated patients, including six responses in 11 patients with recurrent ovarian cancer. Pharmacokinetic studies revealed a systemic clearance (Clss) of 4.5 L/m2/h. This value is consistent with clearances reported for carboplatin administered at lower doses and by different schedules. No evidence for saturation of systemic clearance at higher doses was observed. Carboplatin appears to be an active drug that can undergo considerable dose escalation when used in conjunction with autologous bone marrow support.
Adult↗
Chemotherapy for head and neck cancer: progress and controversy in the management of patients with M0 disease.
The overall survival of patients with advanced squamous cell carcinoma of the head and neck (SCCHN) has not changed despite recent advances in surgical and radiotherapeutic techniques. For most patients with advanced disease, the morbidity associated with conventional surgery or radiotherapy is unacceptably high while the probability of locoregional and distant control of disease is low. The use of chemotherapy with surgery or radiotherapy for patients with SCCHN remains a controversial but highly promising treatment that attempts to improve locoregional control and overall survival or facilitate reductions in the locoregional treatment required for control of disease. Since the early 1960s, numerous trials have evaluated the impact of induction and adjuvant chemotherapy or concurrent chemotherapy and radiotherapy in the management of patients with advanced, but potentially curable, (M0) lesions. While a specific role for chemotherapy in the treatment of patients with SCCHN has not been confirmed by prospective randomized trials, considerable progress in the development of effective therapies has been achieved recently. This progress is characterized by the definition of chemotherapy with increased activity against squamous cell carcinomas and the organization of clinical trials with sufficient power to reach significant conclusions. This article reviews the experience with induction and adjuvant chemotherapy and concurrent chemotherapy and radiotherapy in the multidisciplinary treatment of patients with advanced SCCHN. The potential advantages as well as clinical experience with chemotherapy in these settings are presented.
Antineoplastic Agents↗
Preclinical studies and clinical correlation of the effect of alkylating dose.
Dose-response studies were performed with the alkylating agents [nitrogen mustard, N,N'-bis(2-chloroethyl)-N-nitrosourea, melphalan, cisplatin (CDDP), 4-hydroperoxycyclophosphamide (4-HC), and trimethyleneiminethiophosphoramide] in both the MCF-7 human breast carcinoma cell line and the EMT6 and FSaIIC murine tumor lines. Increasing selection pressure with the alkylating agents CDDP, melphalan, and 4-HC in vitro produced low levels (6.5- to 9-fold) of drug resistance, despite an intensive and prolonged treatment program. The MCF-7 sublines made resistant to CDDP and 4-HC did not exhibit cross-resistance to other alkylating agents; however, the MCF-7 subline resistant to melphalan was partially cross-resistant to nitrogen mustard, 4-HC, and CDDP. A log-linear relationship was maintained between surviving fraction of MCF-7 cells in culture and drug concentration with alkylating agents, whereas for nonalkylating agents the survival curves tended to plateau at high drug concentrations. Log-linear tumor cell kill was also obtained over a wide dosage range with several alkylating agents in murine tumors treated in vivo. Tumor cell survival assay by colony formation indicated the continuing importance of dose in the action of the drugs even at high levels of tumor cell kill. With some agents, there was a difference between the slopes of the tumor cell killing curves in vivo as compared to in vitro. Cyclophosphamide was far more potent in vitro (4-HC) than in vivo (cyclophosphamide). Trimethyleneiminethiophosphoramide and N,N'-bis(2-chloroethyl)-N-nitrosourea were both more potent in vivo than in vitro. These differences may be explained by the various metabolic patterns of these drugs. Dose of alkylating agents is clearly a crucial variable particularly where multilog tumor cell kill is the goal, and in this regard, the effect of drug dose on the tumoricidal action of the alkylating agents is substantially greater than for nonalkylating agents.
Alkylating Agents↗
What's in a name--neoadjuvant.
Explore the source record for details and available documents.
Combined Modality Therapy↗
Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced myelosuppression.
An increase in the dose of chemotherapy enhances the response of many experimental and clinical cancers, but the extent of dose escalation is often limited by myelosuppression. In preliminary trials, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has augmented leukocyte numbers and function, but the optimal dose is not established. We treated 16 adults who had inoperable or metastatic sarcomas with escalating doses of rhGM-CSF before and immediately after a first cycle of chemotherapy (cycle 1) to assess hematologic response and toxicity. A second cycle of chemotherapy (cycle 2) was given without rhGM-CSF. RhGM-CSF was tolerated well at doses of 4 to 32 micrograms per kilogram of body weight per day. At 64 micrograms per kilogram per day, edema and thrombi around a central venous catheter developed in two of four patients. Leukocyte and granulocyte counts increased significantly during the rhGM-CSF infusion. Neutropenia after cycle 1 was significantly less severe and shorter in duration than after cycle 2 (P less than 0.01). Mean total leukocyte and platelet nadirs were 1.0 and 101 x 10(9) per liter for cycle 1 and 0.45 and 44 x 10(9) per liter for cycle 2 (P less than 0.01), and the median intervals from day 1 of chemotherapy to neutrophil recovery (greater than 0.500 x 10(9) per liter) were 15 and 19 days, respectively (P less than 0.01). The duration of neutropenia was 3.5 days with cycle 1 and 7.4 days with cycle 2 (P less than 0.01). We conclude that rhGM-CSF is tolerated well at doses up to 32 micrograms per kilogram per day and is biologically active in leukopenic patients. It merits further evaluation for the prevention of morbidity from chemotherapy.
Adolescent↗
Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study.
Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with direct antitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of 115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 micrograms of rH-TNF/m2. Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNF administered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was hypotension, and five patients treated at the two highest dose levels required dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hour infusions of rH-TNF were associated with significant decreases in serum cholesterol and high-density lipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF, no steady-state level was achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545 micrograms/m2.
Adolescent↗
The crisis in clinical cancer research. Third-party insurance and investigational therapy.
Explore the source record for details and available documents.
Clinical Trials as Topic↗
Combination of N,N',N"-triethylenethiophosphoramide and cyclophosphamide in vitro and in vivo.
In vitro and in vivo studies with the drug combination thioTEPA and cyclophosphamide (CPA) were carried out using the MCF-7 human breast carcinoma cell line and the EMT6 mouse mammary carcinoma cell line. In vitro, survival curves were essentially linear. The EMT6 cell line was less sensitive to thioTEPA than the MCF-7 cell line, with concentrations which reduce cell survival to 10% of 440 and 140 microM, respectively. The response of both cell lines to 4-hydroperoxycyclophosphamide was similar. Simultaneous and immediate sequential treatments with these drugs produced supraadditive cell killing of both cell lines, although the magnitude of the supraadditivity was greater in the MCF-7 cell line than in the EMT6 cell line. Both of these drugs appeared to be as effective as thiol-depleting agents as is diethyl maleate. By DNA alkaline elution, there was a pattern of increasing DNA cross-linking similar to the increasing levels of cytotoxicity of this drug combination with increasing thioTEPA concentrations. In the EMT6 tumor in vivo, the maximally tolerated combination therapy (5 mg/kg x 6 thioTEPA and 100 mg/kg x 3 CPA) produced about 25 days of tumor growth delay which was not significantly different than expected for additivity of the individual drugs. The survival of EMT6 tumor cells after treatment of the animals with various single doses of thioTEPA and CPA was assayed. Tumor cell killing by thioTEPA produced a very steep, linear survival curve through 5 logs. The tumor cell survival curve for CPA out to 500 mg/kg gave linear tumor cell kill through almost 4 logs. In all cases, the combination treatment tumor cell survivals fell well within the envelope of additivity. Both of these drugs are somewhat less toxic toward bone marrow cells by the granulocyte-macrophage colony-forming unit in vitro assay method than to tumor cells. The combination treatments were subadditive or additive in bone marrow granulocyte-macrophage colony-forming unit killing. When bone marrow is the dose-limiting tissue, there is a therapeutic advantage to the use of this drug combination.
Animals↗
Malignant melanoma. Treatment with high-dose combination alkylating agent chemotherapy and autologous bone marrow support.
Nineteen patients with metastatic malignant melanoma were treated with 20 courses of high-dose combination alkylating agent chemotherapy and autologous bone marrow support. All 20 treatment courses were evaluable for toxic reactions and 17 of 20 courses were assessable for response. Twelve of the 20 courses were given at the phase 2 dose per square meter of cyclophosphamide (5.625 g), cisplatin (165 mg), and carmustine (600 mg). Marrow reconstitution occurred with a median time to recovery of 21 and 24 days for more than 500 neutrophils and more than 20,000 platelets, respectively. The overall response rate was 65%, with one patient achieving a complete response with chemotherapy alone. Ten additional patients achieved partial responses following chemotherapy, of which three were subsequently rendered disease free by surgical resection of single areas of residual tumor. Two of these patients are alive and disease free more than 22 months following chemotherapy and one remains relapse free. The median survival for responding patients was 15.2 months and 8.6 months for the entire group.
Adult↗
Molecular characterization of spalt, a homeotic gene required for head and tail development in the Drosophila embryo.
The isolation, identification and structure of the spalt gene is described. This novel homeotic gene of Drosophila is required for the establishment of the posterior-most head and the anterior-most tail segments of the embryo. It encodes a small mRNA of 0.8 kb which is under the control of over 15 kb of upstream sequences as indicated by the phenotype of transformed embryos. The putative spalt protein contains internal repeats and other interesting structural motifs but no homeo box. The spalt transcript accumulates motifs but no homeo box. The spalt transcript accumulates to high levels in the segmental anlagen affected in mutant embryos but is also found in regions of the embryo where no functional requirement has been demonstrated.
Journal Article↗
Development of alkylating agent-resistant human tumor cell lines.
Survival curves and dose escalation studies of four representative human tumor cell lines exposed to the various alkylating agents are presented. With HN2, at a level of one log of cell kill there was a fivefold range in drug concentration required to achieve this degree of cell kill among the cell lines, from 4.5 microM for the SL6 lung adenocarcinoma to 22 microM for the SW2 small-cell lung carcinoma. Four logs of SCC-25 squamous carcinoma cells were killed by 100 microM CDDP; however, there was only about one log of SL6 cells killed by 500 microM CDDP. To kill one log of G3361 melanoma cells required 24 microM 4-HC and to kill one log of SCC-25 cells required 24 microM, approximately a 16-fold difference. The curves for cell kill by L-PAM appeared to be biphasic, with a break at about 100 microM. There was about a threefold range in drug concentration required to achieve one log of cell kill with L-PAM, from 60 microM in the SCC-25 cell line to 18 microM in the SW2 line. To kill one log of SCC-25 cells required 295 microM BCNU and to kill one log of SW2 cell required 120 microM, about a 2.5-fold difference. The range of maximally tolerated HN2 concentrations were from 1200 microM for the SL6 cell line, 48 times the initial concentration, to 300 microM for the SCC-25 line, 16 times the initial concentration. The G3361 line tolerated the highest level of CDDP, 1900 microM, 48 times the initial concentration. The SCC-25 line, on the other hand, tolerated only 600 microM, 30 times the initial concentration. The SL6 cell line maximally tolerated 36 times the initial concentration of 4-HC (1450 microM), whereas the SCC-25 cell line tolerated only 18 times the initial concentration (720 microM). The G3361 melanoma tolerated 1555 microM, 30 times the initial concentration of L-PAM, and the SCC-25 cell line tolerated 700 microM, 14 times the initial concentration. The SL6 cell line tolerated the highest concentration of BCNU, 4200 microM, 24 times the initial concentration. The SCC-25 cell line tolerated 1450 microM, 8 times the initial concentration. In all cases, the SCC-25 cell line was least able to tolerate exposure to increasing concentrations of alkylating agents. The SL6 and G3361 cell lines showed the greatest tolerance for increasing concentrations of alkylating agents.(ABSTRACT TRUNCATED AT 400 WORDS)
Alkylating Agents↗