Targeted cytotoxic luteinizing hormone releasing hormone (LH-RH) analogs inhibit growth of estrogen independent MXT mouse mammary cancers in vivo by decreasing cell proliferation and inducing apoptosis

Karoly Szepeshazi, Andrew V Schally, Attila Nagy, Gabor Halmos, Kate Groot

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Tumor inhibitory action and the optimal dosage regimens of highly potent targeted cytotoxic luteinizing hormone releasing hormone (LH-RH) analogs containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201) were tested in female BDF mice bearing estrogen independent MXT mouse mammary cancers. The effects were compared to those obtained with the cytotoxic radicals DOX or AN-201 alone. Analog AN-207, formed by linking 2-pyrrolino-DOX to [D- Lys6]LH-RH, and analog AN-152, produced by conjugation of DOX to the same carrier, given i.p. as a single injection or repeatedly 2 days apart at their maximum tolerated doses (MTDs) resulted in a 89-93% inhibition of tumor growth. Equimolar amounts of the cytotoxic radicals were toxic. AN-207 and AN-152 likewise had stronger tumor inhibitory effects than their respective cytotoxic radicals AN-201 or DOX alone, when compared at the lower doses corresponding to MTDs of the radicals. Histological evaluation indicated that decreased cell proliferation (shown by mitotic index and AgNOR counts) as well as increased apoptosis (demonstrated by histological and biochemical methods) both contributed to tumor suppression caused by the cytotoxic hormone analogs. Specific, high-affinity LH-RH receptors were present on MXT tumor samples of control untreated mice, but no binding sites for LH-RH could be found on tumor membranes after treatment with the cytotoxic LH-RH analogs. The results suggest that these powerful targeted cytotoxic LH-RH analogs could be considered for treatment of human mammary cancers having receptors for LH-RH.

Original languageEnglish
Pages (from-to)974-987
Number of pages14
JournalAnti-Cancer Drugs
Volume8
Issue number10
StatePublished - Dec 1 1997
Externally publishedYes

Fingerprint

Gonadotropin-Releasing Hormone
Doxorubicin
Estrogens
Cell Proliferation
Apoptosis
Breast Neoplasms
Growth
LHRH Receptors
Neoplasms
Maximum Tolerated Dose
Mitotic Index
Poisons
Binding Sites
Hormones
Injections
Membranes
Therapeutics
AN 204
lysine(6)-doxorubicin LHRH
AN 207

Keywords

  • Apoptosis
  • Cytotoxic LH-RH analogs
  • Experimental breast cancer
  • LH-RH receptors
  • Targeted cancer therapy

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research
  • Oncology

Cite this

Targeted cytotoxic luteinizing hormone releasing hormone (LH-RH) analogs inhibit growth of estrogen independent MXT mouse mammary cancers in vivo by decreasing cell proliferation and inducing apoptosis. / Szepeshazi, Karoly; Schally, Andrew V; Nagy, Attila; Halmos, Gabor; Groot, Kate.

In: Anti-Cancer Drugs, Vol. 8, No. 10, 01.12.1997, p. 974-987.

Research output: Contribution to journalArticle

@article{d4c1ebaac1ea40acb3f28e39494b2222,
title = "Targeted cytotoxic luteinizing hormone releasing hormone (LH-RH) analogs inhibit growth of estrogen independent MXT mouse mammary cancers in vivo by decreasing cell proliferation and inducing apoptosis",
abstract = "Tumor inhibitory action and the optimal dosage regimens of highly potent targeted cytotoxic luteinizing hormone releasing hormone (LH-RH) analogs containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201) were tested in female BDF mice bearing estrogen independent MXT mouse mammary cancers. The effects were compared to those obtained with the cytotoxic radicals DOX or AN-201 alone. Analog AN-207, formed by linking 2-pyrrolino-DOX to [D- Lys6]LH-RH, and analog AN-152, produced by conjugation of DOX to the same carrier, given i.p. as a single injection or repeatedly 2 days apart at their maximum tolerated doses (MTDs) resulted in a 89-93{\%} inhibition of tumor growth. Equimolar amounts of the cytotoxic radicals were toxic. AN-207 and AN-152 likewise had stronger tumor inhibitory effects than their respective cytotoxic radicals AN-201 or DOX alone, when compared at the lower doses corresponding to MTDs of the radicals. Histological evaluation indicated that decreased cell proliferation (shown by mitotic index and AgNOR counts) as well as increased apoptosis (demonstrated by histological and biochemical methods) both contributed to tumor suppression caused by the cytotoxic hormone analogs. Specific, high-affinity LH-RH receptors were present on MXT tumor samples of control untreated mice, but no binding sites for LH-RH could be found on tumor membranes after treatment with the cytotoxic LH-RH analogs. The results suggest that these powerful targeted cytotoxic LH-RH analogs could be considered for treatment of human mammary cancers having receptors for LH-RH.",
keywords = "Apoptosis, Cytotoxic LH-RH analogs, Experimental breast cancer, LH-RH receptors, Targeted cancer therapy",
author = "Karoly Szepeshazi and Schally, {Andrew V} and Attila Nagy and Gabor Halmos and Kate Groot",
year = "1997",
month = "12",
day = "1",
language = "English",
volume = "8",
pages = "974--987",
journal = "Anti-Cancer Drugs",
issn = "0959-4973",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Targeted cytotoxic luteinizing hormone releasing hormone (LH-RH) analogs inhibit growth of estrogen independent MXT mouse mammary cancers in vivo by decreasing cell proliferation and inducing apoptosis

AU - Szepeshazi, Karoly

AU - Schally, Andrew V

AU - Nagy, Attila

AU - Halmos, Gabor

AU - Groot, Kate

PY - 1997/12/1

Y1 - 1997/12/1

N2 - Tumor inhibitory action and the optimal dosage regimens of highly potent targeted cytotoxic luteinizing hormone releasing hormone (LH-RH) analogs containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201) were tested in female BDF mice bearing estrogen independent MXT mouse mammary cancers. The effects were compared to those obtained with the cytotoxic radicals DOX or AN-201 alone. Analog AN-207, formed by linking 2-pyrrolino-DOX to [D- Lys6]LH-RH, and analog AN-152, produced by conjugation of DOX to the same carrier, given i.p. as a single injection or repeatedly 2 days apart at their maximum tolerated doses (MTDs) resulted in a 89-93% inhibition of tumor growth. Equimolar amounts of the cytotoxic radicals were toxic. AN-207 and AN-152 likewise had stronger tumor inhibitory effects than their respective cytotoxic radicals AN-201 or DOX alone, when compared at the lower doses corresponding to MTDs of the radicals. Histological evaluation indicated that decreased cell proliferation (shown by mitotic index and AgNOR counts) as well as increased apoptosis (demonstrated by histological and biochemical methods) both contributed to tumor suppression caused by the cytotoxic hormone analogs. Specific, high-affinity LH-RH receptors were present on MXT tumor samples of control untreated mice, but no binding sites for LH-RH could be found on tumor membranes after treatment with the cytotoxic LH-RH analogs. The results suggest that these powerful targeted cytotoxic LH-RH analogs could be considered for treatment of human mammary cancers having receptors for LH-RH.

AB - Tumor inhibitory action and the optimal dosage regimens of highly potent targeted cytotoxic luteinizing hormone releasing hormone (LH-RH) analogs containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201) were tested in female BDF mice bearing estrogen independent MXT mouse mammary cancers. The effects were compared to those obtained with the cytotoxic radicals DOX or AN-201 alone. Analog AN-207, formed by linking 2-pyrrolino-DOX to [D- Lys6]LH-RH, and analog AN-152, produced by conjugation of DOX to the same carrier, given i.p. as a single injection or repeatedly 2 days apart at their maximum tolerated doses (MTDs) resulted in a 89-93% inhibition of tumor growth. Equimolar amounts of the cytotoxic radicals were toxic. AN-207 and AN-152 likewise had stronger tumor inhibitory effects than their respective cytotoxic radicals AN-201 or DOX alone, when compared at the lower doses corresponding to MTDs of the radicals. Histological evaluation indicated that decreased cell proliferation (shown by mitotic index and AgNOR counts) as well as increased apoptosis (demonstrated by histological and biochemical methods) both contributed to tumor suppression caused by the cytotoxic hormone analogs. Specific, high-affinity LH-RH receptors were present on MXT tumor samples of control untreated mice, but no binding sites for LH-RH could be found on tumor membranes after treatment with the cytotoxic LH-RH analogs. The results suggest that these powerful targeted cytotoxic LH-RH analogs could be considered for treatment of human mammary cancers having receptors for LH-RH.

KW - Apoptosis

KW - Cytotoxic LH-RH analogs

KW - Experimental breast cancer

KW - LH-RH receptors

KW - Targeted cancer therapy

UR - http://www.scopus.com/inward/record.url?scp=0031441622&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031441622&partnerID=8YFLogxK

M3 - Article

VL - 8

SP - 974

EP - 987

JO - Anti-Cancer Drugs

JF - Anti-Cancer Drugs

SN - 0959-4973

IS - 10

ER -