Anthracycline-induced DNA breaks and resealing in doxorubicin-resistant murine leukemic P388 cells.

Energy-dependent drug efflux is believed to be a major factor in cellular resistance to doxorubicin (DOX). However, recent studies have shown that decreased retention alone cannot account for anthracycline resistance, and possibly other factors, such as drug metabolism, free radical scavengers, and altered DNA damage/repair, may be involved. We have measured DOX-induced DNA damage and its repair in P388 cells sensitive (P388/S) and resistant (P388/R) to DOX. Our studies show 2- to 5-fold less DNA damage, measured as protein-associated single-strand DNA breaks, in P388/R cells when compared to similarly treated P388/S cells. The repair of DNA in whole cells, expressed as percent DNA rejoined, was complete in 4 hr in P388/R, whereas no repair was seen in P388/S cells until 20 hr. No difference in repair of DNA lesions was observed when nuclei were used in repair experiments. The absence of repair in sensitive whole cells may be due to high retention or slow drug efflux. Increase of cellular DOX retention by exposure of cells to trifluoperazine (TFP) or verapamil (VPL) did not result in the increase of DNA damage in P388/R cells. DOX analogs, N-trifluoroacetyladriamycin-14-valerate (AD 32), 4'-O-tetrahydropyranyladriamycin (THP-adriamycin), and N-benzyladriamycin-14-valerate (AD 198), induced 2- to 4-fold more DNA damage than DOX in resistant cells. There was no difference in the poly(ADP-ribose) synthesis of P388/S and P388/R cells exposed to DOX or AD 32. Since ADP-ribose polymer synthesis is associated with free radical-induced DNA damage and is indicative of DNA repair by an excision-repair mechanism, data from these studies suggest that DNA breaks in anthracycline-exposed cells may not be due to free radical production but rather to other mechanisms, such as inhibition of DNA topoisomerase II activity. The present studies, in addition to emphasizing the role of DNA damage in resistance, also underscore the relative importance of DNA topoisomerase II function in anthracycline cytotoxicity.

Family life education.

PIP: Family life education is not just instruction of sex and reproduction, but an attitude of love and values that starts from infancy. A child who comes into the world wanted is already loved. Later on, he himself will give love because his 1st contact in the world was a happy one. Most children will go through thumb sucking and masturbation, which is normal and innocent behavior. Toilet training is another important factor in sex education. According to our attitude the child will learn that this part of his body is good or bad. By the age of 3 or 6, children learn to discover the difference in sex from our attitude to each other, and when parents practice double standards, the child is confused and worried. Children's curiousity for knowledge is insatiable. If parents find they are embarressed by their children's questions about sex, it is better to put off answering than to convey the impression that something is not quite nice. 11-year old females should be prepared for menarche with knowledge, and fathers should explain to their sons about voice changes, night emissions and fantasy dreams. Masturbation is normal during adolescence, and the only harm comes from wrong anxiety about it. If 2 young people wish to have premarital intercourse, we must have the courage to tell them that chastity remains a value whether they accept it or not. Education for family life means taking account of the child's attitudes and sex values as a future marriage partner and parent.^ieng

A novel model of a metastatic human breast tumour xenograft line.

The GI-101 human breast tumour xenograft line is unique in that it spontaneously metastasizes to the lungs of athymic murine hosts from subcutaneous trochar implants. Both tumour and lung metastases are positive for normal human breast tissue markers. GI-101 also is positive for the p53 antigen but negative for the c-erbB-2 oncogene.