Modulation of 06-Alkylguanine-DNA Alkyltransferase-mediated Carmustine Resistance Using Streptozotocin

A Phase I Trial

Timothy Panella, David C. Smith, Iriam P. Rogers, Robert L. Fine, Eric P. Winer, Jeffrey Crawford, Donald L. Trump

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

1,3-Bis(2-chloroethyl)-l -nitrosourea (BCNU) resistance may be me-diated by repair of chloroethylated guanine before stable cross-linking occurs. Guanine adducts may be repaired by the enzyme 0-alkylgiianine-DNA alkyltransferase (06-AGAT). Such repair irreversibly inactivates 06-AGAT. Streptozotocin (STZ) forms adducts at the O6 position of guanine; repair of these adducts consumes 06-AGAT. In vivo STZ potentiates BCNU cytotoxicity. The purpose of this trial was to determine the maximum tolerated dose of BCNU that can be administered together with STZ. The STZ dose was 500 mg/m/day for 4 days and was not escalated. BCNU was given 4 h after the third dose of STZ at a starting dose of 75 mg/m. A total of 43 patients were entered in the study. There were 4 dose escalations, reaching a maximum tolerated BCNU dose of 175 mg/m. At this dose, thrombocytopenia was the dose-limiting toxicity (one patient, 25-49 x 109/liter, 2 patients, <25 x 109/liter); neutropenia was less severe (2 patients, 2.0-3.9 x 109/liter, 1 patient, 1.0-1.9 x 107 liter). Two other commonly seen toxicities were elevations in the serum alkaline phosphatase and mild elevations in the serum creatinine. Peripheral blood lymphocyte 06-AGAT levels decreased from a mean of 212 fmol/mg protein pretherapy to 8.2 fmol/mg protein on day 3 prior to BCNU (P = 0.03). Three partial responses were seen. There were no therapy-related fatalities, and toxicity was easily managed. This study established that 150 mg of BCNU can be administered safely together with STZ, 500 mg/m2/day for 4 days. Additional studies are required to determine whether 06-AGAT-mediated BCNU resistance is suppressed.

Original languageEnglish (US)
Pages (from-to)2456-2459
Number of pages4
JournalCancer Research
Volume52
Issue number9
StatePublished - Jan 1 1992
Externally publishedYes

Fingerprint

Carmustine
Streptozocin
Guanine
Maximum Tolerated Dose
DNA alkyltransferase
Neutropenia
Serum
Thrombocytopenia
Alkaline Phosphatase
Creatinine
Proteins
Lymphocytes
Enzymes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Panella, T., Smith, D. C., Rogers, I. P., Fine, R. L., Winer, E. P., Crawford, J., & Trump, D. L. (1992). Modulation of 06-Alkylguanine-DNA Alkyltransferase-mediated Carmustine Resistance Using Streptozotocin: A Phase I Trial. Cancer Research, 52(9), 2456-2459.

Modulation of 06-Alkylguanine-DNA Alkyltransferase-mediated Carmustine Resistance Using Streptozotocin : A Phase I Trial. / Panella, Timothy; Smith, David C.; Rogers, Iriam P.; Fine, Robert L.; Winer, Eric P.; Crawford, Jeffrey; Trump, Donald L.

In: Cancer Research, Vol. 52, No. 9, 01.01.1992, p. 2456-2459.

Research output: Contribution to journalArticle

Panella, T, Smith, DC, Rogers, IP, Fine, RL, Winer, EP, Crawford, J & Trump, DL 1992, 'Modulation of 06-Alkylguanine-DNA Alkyltransferase-mediated Carmustine Resistance Using Streptozotocin: A Phase I Trial', Cancer Research, vol. 52, no. 9, pp. 2456-2459.
Panella, Timothy ; Smith, David C. ; Rogers, Iriam P. ; Fine, Robert L. ; Winer, Eric P. ; Crawford, Jeffrey ; Trump, Donald L. / Modulation of 06-Alkylguanine-DNA Alkyltransferase-mediated Carmustine Resistance Using Streptozotocin : A Phase I Trial. In: Cancer Research. 1992 ; Vol. 52, No. 9. pp. 2456-2459.
@article{edb39b582b704acea4a9d242e8e76423,
title = "Modulation of 06-Alkylguanine-DNA Alkyltransferase-mediated Carmustine Resistance Using Streptozotocin: A Phase I Trial",
abstract = "1,3-Bis(2-chloroethyl)-l -nitrosourea (BCNU) resistance may be me-diated by repair of chloroethylated guanine before stable cross-linking occurs. Guanine adducts may be repaired by the enzyme 0-alkylgiianine-DNA alkyltransferase (06-AGAT). Such repair irreversibly inactivates 06-AGAT. Streptozotocin (STZ) forms adducts at the O6 position of guanine; repair of these adducts consumes 06-AGAT. In vivo STZ potentiates BCNU cytotoxicity. The purpose of this trial was to determine the maximum tolerated dose of BCNU that can be administered together with STZ. The STZ dose was 500 mg/m/day for 4 days and was not escalated. BCNU was given 4 h after the third dose of STZ at a starting dose of 75 mg/m. A total of 43 patients were entered in the study. There were 4 dose escalations, reaching a maximum tolerated BCNU dose of 175 mg/m. At this dose, thrombocytopenia was the dose-limiting toxicity (one patient, 25-49 x 109/liter, 2 patients, <25 x 109/liter); neutropenia was less severe (2 patients, 2.0-3.9 x 109/liter, 1 patient, 1.0-1.9 x 107 liter). Two other commonly seen toxicities were elevations in the serum alkaline phosphatase and mild elevations in the serum creatinine. Peripheral blood lymphocyte 06-AGAT levels decreased from a mean of 212 fmol/mg protein pretherapy to 8.2 fmol/mg protein on day 3 prior to BCNU (P = 0.03). Three partial responses were seen. There were no therapy-related fatalities, and toxicity was easily managed. This study established that 150 mg of BCNU can be administered safely together with STZ, 500 mg/m2/day for 4 days. Additional studies are required to determine whether 06-AGAT-mediated BCNU resistance is suppressed.",
author = "Timothy Panella and Smith, {David C.} and Rogers, {Iriam P.} and Fine, {Robert L.} and Winer, {Eric P.} and Jeffrey Crawford and Trump, {Donald L.}",
year = "1992",
month = "1",
day = "1",
language = "English (US)",
volume = "52",
pages = "2456--2459",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Modulation of 06-Alkylguanine-DNA Alkyltransferase-mediated Carmustine Resistance Using Streptozotocin

T2 - A Phase I Trial

AU - Panella, Timothy

AU - Smith, David C.

AU - Rogers, Iriam P.

AU - Fine, Robert L.

AU - Winer, Eric P.

AU - Crawford, Jeffrey

AU - Trump, Donald L.

PY - 1992/1/1

Y1 - 1992/1/1

N2 - 1,3-Bis(2-chloroethyl)-l -nitrosourea (BCNU) resistance may be me-diated by repair of chloroethylated guanine before stable cross-linking occurs. Guanine adducts may be repaired by the enzyme 0-alkylgiianine-DNA alkyltransferase (06-AGAT). Such repair irreversibly inactivates 06-AGAT. Streptozotocin (STZ) forms adducts at the O6 position of guanine; repair of these adducts consumes 06-AGAT. In vivo STZ potentiates BCNU cytotoxicity. The purpose of this trial was to determine the maximum tolerated dose of BCNU that can be administered together with STZ. The STZ dose was 500 mg/m/day for 4 days and was not escalated. BCNU was given 4 h after the third dose of STZ at a starting dose of 75 mg/m. A total of 43 patients were entered in the study. There were 4 dose escalations, reaching a maximum tolerated BCNU dose of 175 mg/m. At this dose, thrombocytopenia was the dose-limiting toxicity (one patient, 25-49 x 109/liter, 2 patients, <25 x 109/liter); neutropenia was less severe (2 patients, 2.0-3.9 x 109/liter, 1 patient, 1.0-1.9 x 107 liter). Two other commonly seen toxicities were elevations in the serum alkaline phosphatase and mild elevations in the serum creatinine. Peripheral blood lymphocyte 06-AGAT levels decreased from a mean of 212 fmol/mg protein pretherapy to 8.2 fmol/mg protein on day 3 prior to BCNU (P = 0.03). Three partial responses were seen. There were no therapy-related fatalities, and toxicity was easily managed. This study established that 150 mg of BCNU can be administered safely together with STZ, 500 mg/m2/day for 4 days. Additional studies are required to determine whether 06-AGAT-mediated BCNU resistance is suppressed.

AB - 1,3-Bis(2-chloroethyl)-l -nitrosourea (BCNU) resistance may be me-diated by repair of chloroethylated guanine before stable cross-linking occurs. Guanine adducts may be repaired by the enzyme 0-alkylgiianine-DNA alkyltransferase (06-AGAT). Such repair irreversibly inactivates 06-AGAT. Streptozotocin (STZ) forms adducts at the O6 position of guanine; repair of these adducts consumes 06-AGAT. In vivo STZ potentiates BCNU cytotoxicity. The purpose of this trial was to determine the maximum tolerated dose of BCNU that can be administered together with STZ. The STZ dose was 500 mg/m/day for 4 days and was not escalated. BCNU was given 4 h after the third dose of STZ at a starting dose of 75 mg/m. A total of 43 patients were entered in the study. There were 4 dose escalations, reaching a maximum tolerated BCNU dose of 175 mg/m. At this dose, thrombocytopenia was the dose-limiting toxicity (one patient, 25-49 x 109/liter, 2 patients, <25 x 109/liter); neutropenia was less severe (2 patients, 2.0-3.9 x 109/liter, 1 patient, 1.0-1.9 x 107 liter). Two other commonly seen toxicities were elevations in the serum alkaline phosphatase and mild elevations in the serum creatinine. Peripheral blood lymphocyte 06-AGAT levels decreased from a mean of 212 fmol/mg protein pretherapy to 8.2 fmol/mg protein on day 3 prior to BCNU (P = 0.03). Three partial responses were seen. There were no therapy-related fatalities, and toxicity was easily managed. This study established that 150 mg of BCNU can be administered safely together with STZ, 500 mg/m2/day for 4 days. Additional studies are required to determine whether 06-AGAT-mediated BCNU resistance is suppressed.

UR - http://www.scopus.com/inward/record.url?scp=0026611148&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026611148&partnerID=8YFLogxK

M3 - Article

VL - 52

SP - 2456

EP - 2459

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 9

ER -