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Purpose: We performed a phase I trial of piroxantrone with and without granulocyte colony-stimulating factor (G-CSF) to determine whether the use of this cytokine would enable us to increase the dose-intensity of piroxantrone., Patients and Methods: Thirty-eight patients received 121 courses of piroxantrone administered once every 21 days. Initial patient cohorts received piroxantrone alone starting at 150 mg/m2 and the dose was escalated in subsequent patients until dose-limiting toxicity (DLT) was reached. Patient cohorts then received escalating doses of piroxantrone starting at 185 mg/m2 administered with G-CSF beginning day 2., Results: Dose-limiting neutropenia occurred in three of six patients treated with 185 mg/m2 piroxantrone; the maximum-tolerated dose (MTD) of piroxantrone alone was 150 mg/m2. Three of six patients treated with piroxantrone and G-CSF exhibited dose-limiting thrombocytopenia at 445 mg/m2; the MTD of piroxantrone with G-CSF was thus 355 mg/m2. Seven patients developed symptomatic congestive heart failure (CHF) at cumulative piroxantrone doses ranging from 855 to 2,475 mg/m2 and two have died of cardiotoxicity. Of these patients, six of seven had previously received doxorubicin. Other nonhematologic toxicity was mild., Conclusion: The use of G-CSF results in a more than twofold increase in the MTD of piroxantrone. However, symptomatic cardiotoxicity is prominent, especially in patients who have received prior treatment with anthracyclines.

Piroxantrone is an anthrapyrazole derivative with broad antitumor activity in vitro. In previous phase I trials, the dose-limiting toxicity of this agent was myelosuppression. Therefore, a phase I and pharmacokinetic study of a 1-h infusion of piroxantrone in combination with granulocyte-colony stimulating factor was conducted. In this article, we report the results of the pharmacokinetic analysis. Thirty-seven patients were studied over a dosage range of 150 to 555 mg/m2. The plasma elimination of piroxantrone was biexponential with a mean (+/- SD) t1/2 alpha of 3.2 +/- 2.7 min and a mean (+/- SD) t1/2 beta of 82 +/- 92 min. Clearance was 840 +/- 230 ml/min/m2. A limited sampling strategy was developed to allow the estimation of total drug exposure (area under the plasma concentration-time curve) from the plasma piroxantrone concentrations at 30, 60, and 120 min after the start of the infusion. The pharmacokinetic behavior of a presumed piroxantrone metabolite not previously described in plasma was also characterized. Based on in vitro cytotoxicity studies with partially purified extract of this compound, we do not believe that it contributes to the antitumor effects of piroxantrone at the concentrations observed in plasma. Finally, piroxantrone elimination was linear over the nearly 4-fold dose range studied, indicating that when dose adjustments are made, systemic drug exposure will remain predictable.

Background: Typhlitis is being recognized with increasing frequency as a serious complication of aggressive chemotherapy for hematologic and solid malignancies., Methods: In this report the authors describe two cases of typhlitis in patients with metastatic breast cancer treated with taxol and doxorubicin., Results: Both cases occurred during the first cycle of treatment with taxol (180 mg/m2) and doxorubicin (75 mg/m2), being given simultaneously as 72-hour continuous intravenous infusions., Conclusion: Two cases of typhlitis have occurred after combined treatment with taxol and doxorubicin, while typhlitis has not been described after treatment with either drug alone.

Fazarabine (Arabinofuranosyl-5-azacytosine) is a synthetic pyrimidine nucleoside which combines the arabinose sugar of cytosine arabinoside with the triazine base of 5-azacytidine. It has demonstrated activity against a variety of human solid tumor xenografts including colon, lung and breast cancers. Eighteen patients with refractory metastatic colon cancer were enrolled in a phase II trial of fazarabine. The drug was administered as a 72 hr continuous infusion every 3-4 weeks; the starting dose was 2 mg/m2/hr as established in a previous phase I study. The major toxicity was neutropenia, as predicted from the phase I study. The median time to nadir for cycle 1 was 20 days, with a median granulocyte count of 437/microliters (range 36-1600/microliters); recovery was within 2-4 days, with only one incidence of fever and neutropenia in 42 cycles. Especially noted for their absence were thrombocytopenia, nausea, vomiting and stomatitis. No objective clinical responses were seen; one patient had stabilization of rapidly growing liver metastases for a period of 7 months. In view of fazarabine's narrow range of toxicities, future dose intensification trials utilizing fazarabine in combination with hematopoietic growth factors are worthy of consideration.

The objective of this phase I trial was to determine the maximal tolerated dose (MTD) of Taxol and doxorubicin administered as a simultaneous intravenous infusion over 72 hours every 21 days. Granulocyte-colony stimulating factor (G-CSF) 10 micrograms/kg, was administered on days 4-18 of each cycle. The treated population consisted of metastatic breast cancer patients previously untreated with chemotherapy for metastatic disease, who had not received doxorubicin in the adjuvant setting and who had bidimensionally measurable disease. The MTD was determined to be 75 mg/m2 of doxorubicin and 160 mg/m2 of Taxol. The dose-limiting toxicity of the combination was clinical typhlitis in three of three patients. Other significant toxicities included grade 3 diarrhea at the higher dose levels and grade 4 neutropenia in all patients. Eighteen patients were treated on this initial phase I study. The overall response rate was 62%, with 6% complete responses and 56% partial responses. The combination of doxorubicin and Taxol by 72-hour continuous infusion with G-CSF is an active regimen in patients with metastatic breast cancer.

One hundred and seven patients with locally advanced breast cancer were prospectively referred for multimodality treatment on protocol using chemohormonal therapy to maximal response followed by local treatment and maintenance therapy. Forty-eight patients (45%) were diagnosed with Stage IIIA disease, 46 (43%) with Stage IIIB inflammatory cancer, and 13 (12%) with Stage IIIB non-inflammatory disease. Induction therapy consisted of cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil with hormonal synchronization using tamoxifen and conjugated estrogens. Local treatment was determined by response to chemotherapy. Patients with a clinical parital response underwent mastectomy followed by local-regional radiotherapy while patients with a clinical complete response were biopsied for pathologic correlation. Those with residual disease received mastectomy followed by radiotherapy while those with a pathologic complete response received radiation only to the intact breast and regional nodes. With a median follow-up of 64 months, patients with IIIA disease had a significantly lower local-regional failure rate compared to IIIB inflammatory patients, with the 5-year actuarial local-regional failure rate as only site of first failure 3% for IIIA disease versus 21% for IIIB inflammatory cancer (p = .02), and local-regional failure as any component of first failure 12% versus 36% (p = .01), respectively. When local-regional failure was analyzed by repeat biopsy, 5/31 (16%) patients with a pathologic complete response treated with radiation only developed a local-regional failure versus 2/53 (4%) with residual disease treated with mastectomy and postoperative radiotherapy. The 5-year actuarial local-regional failure rate as first site of failure was 23% for radiation only versus 5% for mastectomy and post-operative radiotherapy (p = .07). The response to chemotherapy did not reliably predict local-regional control. Both relapse-free survival and overall survival were significantly better for IIIA versus IIIB patients; stratification by repeat biopsy did not however, significantly affect either relapse-free or overall survival.

Expeditious clinical development and approval of new drugs that are beneficial to patients are matters of high priority. There has been a great deal of discussion within the oncology community about what should constitute evidence of effectiveness of new anticancer agents for purposes of drug approval. This commentary is intended to illustrate a variety of end points that can lead to approval of new anticancer agents for specific clinical situations. Although the ultimate hope of antineoplastic therapy is prolongation of life, there are other effects of anticancer drugs that constitute clear clinical benefit and represent evidence of effectiveness. The guiding principle is that the beneficial effects obtained from a new drug should sufficiently outweigh the adverse effects such that the potential risk:benefit ratio achieved by an individual patient is favorable. The assessment of a new drug should flexibly evaluate safety and efficacy in the context of the specific clinical condition being treated. Early discussions with the Food and Drug Administration (FDA) and the National Cancer Institute (NCI) are recommended to identify prospectively the end points and trial designs needed to demonstrate effectiveness of a new drug. The general principles discussed will likely apply to the drug approval process for other medical disciplines as well.

We have compared in different human neuroblastoma cell lines and human glioblastoma cells the expression level, structure, and tyrosine-specific protein kinase activity of pp60c-src. Our results show that not all human neuroblastoma cell lines express pp60c-src molecules with amino-terminal structural alterations. In neuroblastoma cells which possess pp60c-src with altered gel migration, the diminished polyacrylamide gel mobility of pp60c-src was found not to be dependent upon amino-terminal phosphorylations since extensive treatment of these molecules with phosphatase did not significantly change their gel migration properties. Similar differences in gel migration were observed when RNA from the various neuroblastoma and glioblastoma cells was translated in vitro using either rabbit reticulocyte or wheat germ lysates. White the level of c-src mRNA in the different cells analyzed was found to be similar, the abundance of pp60c-src in these same cells was found to vary by as much as 12-fold. This suggests that the abundance of pp60c-src in human neuroendocrine tumors is regulated through post-transcriptional and/or post-translational events which may be related to the stage of neuronal differentiation of the cells. Based upon determination of pp60c-src abundance by immunoblot analysis, we demonstrate that pp60c-src molecules derived from human neuroblastoma and glioblastoma cells have very similar in vitro protein kinase activities.

We examined the expression, abundance, and protein kinase activity of pp60c-src in two different pairs of genetically indistinguishable cloned human neuroblastoma cell variants which display altered phenotypes as the result of conversion from a neuronal to a non-neuronal phenotype. The results demonstrate that cells which exhibit the neuroblastic (N-type) phenotype possess high levels of pp60c-src protein and that one of the two N-type cell lines is capable of expressing the neuronal-specific isoenzyme of pp60c-src. In contrast, cells which display the substrate-adherent (S-type) phenotype have low levels of pp60c-src protein and express exclusively the non-neuronal isoenzyme of pp60c-src. In all cells examined the abundance of pp60c-src was found to be proportional to the steady-state level of c-src RNA. In each case the protein kinase activity of pp60c-src was found to be proportional to the abundance of the protein and independent of the ratio of neuronal to non-neuronal species of pp60c-src.

Because there is elevation of pp60c-src activity in breast carcinoma tissue, we analyzed primary breast cancer tissue samples from 30 women to determine whether pp60c-src activity correlated with specific clinical parameters. We found that tumors with a progesterone receptor had higher pp60c-src activity than tumors without such a receptor. But there was no association of pp60c-src activity with the presence of an estrogen receptor or of nodes, or with menopausal status or age. The function of pp60c-src in normal cells and in breast cancer is unknown, as is the significance of our finding of an association of elevated pp60c-src activity and the presence of progesterone receptors.

Methotrexate pretreatment of L1210 cells had been shown previously by us to cause an enhancement of the intracellular accumulation of 5-fluorouracil and of the formation of 5-fluorouracil nucleotides which was correlated with synergistic cytotoxicity. This effect of methotrexate was associated with increases in 5-phosphoribosyl-1-pyrophosphate, the cofactor required for the conversion of 5-fluorouracil to 5-fluorouridine-5'-monophosphate (FUMP). Because these influences on 5-fluorouracil metabolism were most likely mediated by the activity of methotrexate as an inhibitor of purine synthesis, the effects of other agents that inhibit purine synthesis were examined. An inhibitor of amidophosphoribosyltransferase, 6-methylmercaptopurine ribonucleoside, the glutamine antagonists, azaserine and 6-diazo-5-oxo-L-norleucine (DON), and the L-aspartate analogue inhibitor of adenylsuccinate synthetase, L-alanosine, all reduced the incorporation of [1-14C]glycine into adenine and guanine bases isolated from nucleic acids. Each drug also resulted in intracellular elevations of 5-phosphoribosyl-1-pyrophosphate that were 15- to 25-fold greater than control levels. These alterations in de novo purine nucleotide synthesis were associated with enhanced intracellular 5-fluorouracil accumulation and synergistic cytotoxicity.

The relative abundance of pp60c-src molecules associated with polyomavirus (Py) middle tumor antigen (MTAg) and the relative abundance of MTAg associated with pp60c-src in a variety of Py-transformed rat cells was determined by quantitative immunoblot analyses which detect pp60c-src or Py MTAg. The results demonstrate that approximately 5 to 10% of the total immunoprecipitable pp60c-src molecules in Py-transformed rat cells are stably associated with MTAg and have elevated protein kinase activities. In these same cells, it was found that approximately 10 to 15% of the detectable MTAg molecules are stably associated with pp60c-src. Other results presented in this report demonstrate that approximately 50 to 75% of the total MTAg-associated cellular tyrosine kinase activity potentially represents the enzymatic activity of pp60c-src, while the remaining 25 to 50% represents the activity of other cellular tyrosine kinases. Our results also show that most pp60c-src molecules associated with Py MTAg do not possess electrophoretic mobilities that are altered from those of pp60c-src molecules not associated with MTAg or pp60c-src molecules obtained from normal rodent cells.

A strike of registered nurses in a large voluntary teaching hospital required changes in prehospital and emergency department delivery of services. An explanation of how the strike was handled by one emergency department is offered, as are comments on implications for emergency physicians and lessons for future strike situations.