© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 2, 101,
January 20, 1999
© 1999 Oxford University Press
IN THIS ISSUE |
Simian virus 40 (SV40), a polyomavirus that originated in rhesus monkeys, was discovered as a contaminant of polio vaccines given to millions of people from 1955 through 1963. This virus has been studied extensively since its discovery and has been shown to induce tumors in rodents and to transform many types of cultured cells, including human cells. However, it is not clear whether SV40 produces tumors in humans. Butel and Lednicky (p. 119) review various aspects of SV40 replication and cell transformation, and they discuss the implications for human disease. The authors conclude that evidence of SV40 DNA in certain human cancers is persuasive but that additional evidence is required to prove that the virus plays a causative role in human disease.
Viral Vector Boosts Immunity to Tumors
Some evidence indicates that simian virus 40 (SV40) is associated with several lethal human cancers, including brain tumors, mesotheliomas, and osteosarcomas, among others, primarily because an SV40-specific protein, SV40 T antigen, has been detected in these cancers. Xie et al. (p. 169) have constructed a recombinant vaccinia virus that encodes a safety-modified T antigen that elicits an immune response against cells expressing T antigen in mice. The authors report that this immune response protects mice against a lethal tumor challenge and results in a possible therapeutic effect against tumors that express T antigen. They conclude that the recombinant virus offers a new avenue for the development of therapies for human cancers that express the tumor-associated antigen T antigen.
Blocking Oncoprotein Activity
The precise mechanism by which the Bcr/Abl oncoprotein transforms normal hematopoietic cells into leukemic cells is unknown. Nevertheless, it is well accepted that the enhanced tyrosine kinase activity of the Bcr/Abl fusion protein is crucial to the process. le Coutre et al. (p. 163) used tumor-bearing nude mice that had been injected with Bcr/Abl-positive human leukemic cell lines KU812 or MC3 to evaluate the antineoplastic activity of a chemical compound named CGP57148B, which is a competitive inhibitor of the Bcr/Abl tyrosine kinase. The authors found that a treatment regimen assuring the continuous block of the phosphorylating activity of the Bcr/Abl oncogenic tyrosine kinase and administered over 11 days cured 87%-100% of treated mice.
In an editorial, Sausville (p. 102) says that the results represent a milestone and a guide for developing protein kinase for cancer treatment. He calls the experiments of le Coutre et al. "meticulously conducted," saying they "promise a new paradigm for cancer drug development." At the same time, Sausville urges caution: Mouse models can be unreliable in predicting the utility of a particular treatment to human patients.
Inducing Kaposi's Sarcoma Cell Death
Isolation of Kaposi's sarcoma (KS) cell lines (e.g., KS Y-1) has furthered understanding of the pathogenesis of KS and revealed that inhibition of this cancer in mice occurs in early pregnancy and after treatment with certain commercial preparations of human chorionic gonadotropin (hCG, a pregnancy hormone purified from urine). The activity of these preparations has been attributed to an hCG-associated factor (HAF). While several clinical benefits of HAF are clearly evident, the basis for its anti-KS properties has remained unknown. Samaniego et al. (p. 135) have found that the anti-KS activity of HAF appears to be responsible for inducing apoptosis (programmed cell death). Such activity suggests that HAF may be the factor in pregnancy-related regulation of cell death.
In an editorial, Darzynkiewicz (p. 104) focuses on the molecular identity of HAF. He says that available evidence points in two directions: 1) that HAF is a low-molecular-weight (2-4 kd) contaminant in hCG preparations—possibly a degradation product of hCG itself—and 2) that HAF is a larger contaminant, an approximately 18-kd ribonuclease, that is selectively cytotoxic for KS cells.
Antisense: Suppressing the Suppressor?
Thrash-Bingham and Tartof (p. 143) have discovered a naturally
occurring antisense RNA that is overexpressed in one specific form of kidney cancer:
nonpapillary clear cell renal carcinoma. They hypothesize that this overexpressed transcript may
be responsible for loss of normal p53 tumor suppressor function in these carcinomas, thus
permitting uncontrolled cell growth. The antisense transcript, which they call aHIF, is able to
bind to sequences at the 3' end of hypoxia inducible factor alpha (HIF1
) messenger
RNA. Such binding could impair a cell's ability to make HIF1 protein, which has
two known functions: 1) to act as a transcription factor for hypoxia-inducible genes—that
is, genes that become active when a cell's oxygen level falls below normal—and 2)
to stabilize p53 protein during hypoxic conditions.
In an accompanying editorial, Neckers (p. 106) suggests that
Thrash-Bingham and Tartof may have discovered an alternative mechanism for activating
hypoxia-survival genes while at the same time preventing hypoxic induction of HIF1. He
says aHIF may be the missing link between HIF1 (which is responsible for the
transcriptional activation of hypoxia-response genes) and the von Hippel-Lindau protein, pVHL
(which prevents expression of these same genes under normal aerobic conditions).
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