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High-dose chemotherapy with BCNU, melphalan, or both, followed by autologous bone marrow transplantation (ABMT) has been reported to produce response rates in excess of 60% in patients with advanced melanoma. We tested doses of BCNU associated with reversible bone marrow toxicity and acceptable extramedullary toxicity without the use of ABMT in 19 patients with a diagnosis of advanced malignant melanoma. All patients were evaluable for toxicity and 18 were evaluable for response; one patient had a new primary tumor. The patient population had a median age of 44 years (range, 16 to 71) and a median Karnofsky performance status of 80 (range, 50 to 100). Ten were women and nine were men, all had visceral dominant disease, and none had received previous chemotherapy. Our purpose was to test the feasibility of treatment without ABMT, its toxicity and efficacy, and the possibility of administering sequential repeated courses of therapy. Vincristine was added to the regimen to potentially increase efficacy. Treatment consisted of BCNU (750 mg/m2) and vincristine (2 mg days 1 and 8). Six patients who recovered bone marrow function received melphalan (60 mg/m2) and vincristine (2 mg days 1 and 8). Twenty-two percent (95% confidence limits, 3% to 39%) of patients had remissions (all partial) and these were of short duration. Toxicity was substantial with 16% early lethality and 29% incidence of lethal drug-related complications. Two patients (11%) died toxic after a second course of BCNU. Our results suggest that there is no practical role for high-dose BCNU in the treatment of melanoma.

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Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.5.1495 ◽

1996 ◽

Vol 14 (5) ◽

pp. 1495-1503 ◽

Cited By ~ 45

Author(s):

S J Clarke ◽

J Hanwell ◽

M de Boer ◽

A Planting ◽

J Verweij ◽

...

Keyword(s):

Bone Marrow ◽

Liver Function ◽

Phase I ◽

Thymidylate Synthase ◽

Liver Toxicity ◽

Response To Treatment ◽

Repeated Treatment ◽

Bone Marrow Toxicity ◽

Phase Ii Trials ◽

Advanced Malignancy

PURPOSE To perform a phase I clinical and pharmacologic study of ZD1694 (Tomudex, Alderley Park, United Kingdom), a new folate-based thymidylate synthase (TS) inhibitor, in patients with advanced malignancy. PATIENTS AND METHODS From February 1991 to January 1993, 61 patients with a range of solid tumor received 161 courses of ZD1694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating doses from 0.1 to 3.5 mg/m2. Pharmacokinetic (PK) analysis was performed with the first two courses of treatment. There were 33 men and 28 women with a median age of 53 years (range, 21 to 73). Fifty-five patients (90%) had previously received chemotherapy. RESULTS Reversible liver toxicity and dose-related gastrointestinal (GI) and bone marrow toxicity occurred at > or = 1.6 mg/m2. Liver function usually returned to normal with repeated treatment, but GI and bone marrow toxicities generally became more severe. No renal toxicity was observed. The maximum-tolerated dose (MTD) was 3.5 mg/m2, at which, in addition to antiproliferative toxicities, four of six patients (67%) developed severe malaise that consisted of anorexia, nausea, and asthenia, with rapidly decreasing performance status that limited re-treatment. Abnormal liver function was also seen in four patients (67%). At 3.0 mg/m2, grades III and IV diarrhea were seen in six of 23 patients (26%) and grade IV myelosuppression in two others. Liver toxicity was self-limiting and not associated with severe malaise. Two patients had a partial response to treatment. PK analysis showed that plasma elimination was triexponential, with pronounced variability in the mean terminal half-life (t1/2gamma) for a given dose ranging from 8.2 to 105 hours. There was a linear relationship between dose and both the area under the concentration-time curve (AUC) and maximum concentration (Cmax), but no clear association between these parameters and response or toxicity. CONCLUSION The dose of ZD1694 recommended for phase II trials is 3.0 mg/m2.

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Correlation of nitrosourea murine bone marrow toxicity with deoxyribonucleic acid alkylation and chromatin binding sites

Biochemical Pharmacology ◽

10.1016/0006-2952(82)90667-0 ◽

1982 ◽

Vol 31 (9) ◽

pp. 1671-1679 ◽

Cited By ~ 9

Author(s):

Dianna Green ◽

Kenneth D. Tew ◽

Takashi Hisamatsu ◽

Philip S. Schein

Keyword(s):

Bone Marrow ◽

Binding Sites ◽

Deoxyribonucleic Acid ◽

Bone Marrow Toxicity ◽

Chromatin Binding ◽

Acid Alkylation ◽

Murine Bone Marrow

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Quantifying Drug‐Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model

CPT Pharmacometrics & Systems Pharmacology ◽

10.1002/psp4.12459 ◽

2019 ◽

Vol 8 (11) ◽

pp. 858-868 ◽

Cited By ~ 6

Author(s):

Chiara Fornari ◽

Lenka Oplustil O'Connor ◽

Carmen Pin ◽

Aaron Smith ◽

James W.T. Yates ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Toxicity ◽

Systems Pharmacology ◽

Drug Induced ◽

Systems Pharmacology Model

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Purine versus non-purine xanthine oxidase inhibitors against cyclophosphamide-induced cardiac and bone marrow toxicity in rats

Human & Experimental Toxicology ◽

10.1177/0960327119883412 ◽

2019 ◽

Vol 39 (3) ◽

pp. 249-261 ◽

Cited By ~ 2

Author(s):

AA El-Sheikh ◽

WY Abdelzaher ◽

AA Gad ◽

SA Abdel-Gaber

Keyword(s):

Bone Marrow ◽

Creatine Kinase ◽

Xanthine Oxidase ◽

Bone Marrow Toxicity ◽

Histopathological Changes ◽

Xanthine Oxidase Inhibitors ◽

Creatine Kinase Mb ◽

Life Threatening ◽

Hematopoietic Toxicity ◽

Serious Disease

Background and aim: Cancer is a fatal and serious disease. Cyclophosphamide (CYC) is a commonly used anticancer drug. Cardiotoxicity and myelotoxicity are life-threatening side effects of CYC treatment. We aimed to evaluate the effect of the xanthine oxidase (XO) inhibitors, allopurinol (ALL) and febuxostat (FEB), on CYC-induced cardio- and hematopoietic toxicity in rats. Methods: ALL (100 mg/kg/day) or FEB (10 mg/kg/day) were administered orally to rats in the presence and absence of CYC (200 mg/kg kg i.p. single dose) treatment. Serum creatine kinase-MB creatine kinase myocardial band (CK-MB) and lactate dehydrogenase (LDH) activities were estimated. Complete blood counting (CBC), cardiac and bone marrow XO activity, malondialdehyde level, and superoxide dismutase activity were determined. Cardiac and bone marrow histopathological changes were also evaluated. Results: ALL and FEB significantly decreased CK-MB and LDH induced by CYC. Disturbed levels of XO, oxidative stress parameters, and CBC were also corrected by both XO inhibitors tested, with amelioration of cardiac histopathological changes caused by CYC. Treatment with FEB, but not ALL, prior to CYC challenges normalized bone marrow histopathological changes. Conclusion: These results suggest that both XO inhibitors tested; ALL and FEB can ameliorate CYC-induced cardiotoxicity. However, only FEB can protect against CYC-induced myelotoxicity, whereas ALL, to the contrary, might aggravate it.

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Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group study.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.1.193 ◽

1997 ◽

Vol 15 (1) ◽

pp. 193-198 ◽

Cited By ~ 104

Author(s):

A Jakobsen ◽

K Bertelsen ◽

J E Andersen ◽

H Havsteen ◽

P Jakobsen ◽

...

Keyword(s):

Ovarian Cancer ◽

Bone Marrow ◽

Epithelial Ovarian Cancer ◽

Dose Intensity ◽

Dose Effect ◽

Fixed Dose ◽

Bone Marrow Toxicity ◽

Significant Difference ◽

Carboplatin Dose ◽

Carboplatin Auc

PURPOSE To elucidate the effect of a doubled carboplatin dose-intensity in epithelial ovarian cancer in combination with a fixed dose of cyclophosphamide. PATIENTS AND METHODS A total of 222 patients with epithelial ovarian cancer stages II to IV were included in the study. Following surgery, patients were randomly assigned to receive carboplatin at an area under the concentration-versus-time curve (AUC) of 4 (AUC4) or carboplatin at an AUC of 8 (AUC8) and cyclophosphamide 500 mg/m2 given every 4 weeks for six courses. The AUC was calculated according to Calvert's formula. In 123 patients, the carboplatin AUC was also measured based on a single-sample method and the results were compared with the calculated AUC. The end points of the trial were complete pathologic remission (CPR) and crude survival. RESULTS Approximately 50% of patients in both arms underwent second-look surgery. The frequency of CPR was 32% and 30%, respectively. The survival curves showed no significant difference (P = .84). The dose-intensity of cyclophosphamide was almost identical in the two arms, whereas that of carboplatin was different. In the AUC8 arm, the dose-intensity was 1.86 times that of the AUC4 arm. The results also demonstrated good agreement between the calculated and the measured AUC in most patients. Bone marrow toxicity was significantly higher in the AUC8 arm. CONCLUSION A doubling of the carboplatin dose-intensity did not result in any significant improvement of pathologic remission or survival. Calvert's formula can be used to give a fairly accurate estimate of the carboplatin AUC. Bone marrow toxicity increased with higher dose-intensity, and a further increase of dose is only feasible with growth-factor or stem-cell support.

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