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Biomedical subjects

K K Ang

Publications and source records attributed to K K Ang.

At least 145 records · Page 8Linked to original sources
PubMed1988

Proliferation kinetics of a murine fibrosarcoma during fractionated irradiation.

Accelerated growth of tumor clonogens during the course of fractionated irradiation has been considered one of the major causes of radiation treatment failure. Alterations in clonogen growth rate could occur through three basic mechanisms: changes in cell-loss factor, changes in cell-cycle time, and recruitment of previously quiescent cells into the proliferative pool. This study was designed to assess changes in the cell-cycle time of clonogens of a murine fibrosarcoma during fractionated irradiation using an artificial pulmonary micrometastasis model. Lung colonies of various ages (4 h, 1 day, or 4 days) were exposed to single doses of irradiation ranging from 5-13 Gy; the fraction of surviving colonies was used to determine the preirradiation growth kinetics. The growth kinetics during fractionated irradiation was derived from colony-survival data of 4-day-old micrometastasis exposed to single doses or to 2, 5, 9, and 15 fractions separated by 4, 12, or 24-h intervals. The size of dose fractions used ranged from 1.7 to 14 Gy. The estimated clonogen doubling times before irradiation and during overall treatment periods of up to 14 days were 0.71 and 1.1 days, respectively. This significant (P less than 0.0001) increase in the doubling time was most likely a consequence of lengthening of the overall cell-cycle time of the clonogens by radiation-induced division delay. This observation suggests that accelerated growth, when it occurs in some tumors during fractionated treatment, is the result of a decreased cell-loss factor or recruitment of quiescent cells, but not a shortening of the cell-cycle time of the clonogens.

Animals↗
PubMed1987

Is the rate of repair of radiation-induced sublethal damage in rat spinal cord dependent on the size of dose per fraction?

In the present study the possible dependency of the kinetics of repair of sublethal damage in rat spinal cord on the fraction size has been further investigated. A wide range of sizes of dose per fraction (1.7-17.5 Gy) has been given with interfraction intervals varying from 0.5 to 24 hr. A direct method for analysis of quantal response and an incomplete-repair (IR) model for survival after fractionated exposures with short intervals were used to interpret the data. The half time of repair (T1/2) was found to be 1.6, 1.6 and 1.9 hrs for fraction sizes of approximately 4, 9, and 14 Gy respectively. There appears to be no significant effect of fraction size on the rate of repair. A clinically relevant feature observed from these experimental data is that in this tissue it takes more than 4 hrs for repair of sublethal damage, induced by a dose of approximately 4 Gy, to approach completion (i.e., sparing beyond the limit of the experimental resolution). This has to be taken into account when several fractions are to be given each day. Another feature noted from the analysis of these results is that the alpha/beta determined from the complete repair data is considerably smaller than that estimated from the incomplete repair data (interval less than or equal to 4 hrs). The nature of the inconsistency is discussed.

Animals↗
PubMed1987

Ketoconazole therapy for advanced prostatic cancer: feasibility and treatment results.

To investigate the feasibility and antitumoral effect of ketoconazole in the treatment of disseminated prostatic cancer, 22 patients with stage D2 disease were treated with 400 mg. ketoconazole orally every 8 hours. Of the 17 patients evaluable for antitumoral effect an initial tumor response of 88 per cent was observed (1 complete and 8 partial responses, and 6 with stable disease) with a mean duration of 15.8 months (range 5 to more than 30 months). Treatment-related side effects were encountered in 21 patients and consisted of asthenia, gastrointestinal complaints, skin reactions and cardiovascular complications. They were judged to be mild in 8 patients, moderate in 5 and severe in 8. Treatment had to be discontinued because of side effects in 7 patients (32 per cent). During treatment with ketoconazole serum testosterone levels decreased rapidly and attained nearly castrate levels at the end of week 3. However, after 1 month a steady increase was noted and the testosterone levels reached low normal ranges after 5 months. No hormonal or biochemical indications of adrenocortical insufficiency were noted. High dose ketoconazole is effective in the treatment of disseminated prostatic cancer. Its use is limited by the side effects and the inability to maintain castrate levels of testosterone.

Adenocarcinoma↗
PubMed1987

The effect of small radiation doses per fraction on mouse lip mucosa assessed using the concept of partial tolerance.

The acute effect of small radiation doses per fraction on mouse lip mucosa was investigated in the present study. In order to minimize the amount of additional sparing by regeneration during fractionated irradiations in this rapidly proliferating tissue, the overall treatment time had to be limited to at most 4 days, so that the number of irradiations that could be delivered was limited. Therefore, the concept of partial tolerance, established in the rat spinal cord model, was applied. The present experimental data confirm the validity of using this concept for assessing the effect of small radiation doses on tissues. The results of experiments covering a wide range of fraction sizes show that the isoeffective dose for a given mucosal reaction increases when the dose per fraction is progressively decreased to about 2 Gy per fraction. Further reduction of the size of dose per fraction, however, does not result in a detectable extra increase in the total dose to produce the same level of biological effect. It seems that the dose limit of sparing by fractionation in this rapidly proliferating normal tissue might be situated at larger fraction sizes than 0.6 Gy as estimated on basis of the mathematical linear-quadratic model, using an alpha/beta ratio of 6 Gy measured from data with doses per fraction in the range of 2 to 10 Gy.

Animals↗
PubMed1987

Immunological and clinical observations in diabetic kidney graft recipients pretreated with total-lymphoid irradiation.

In a feasibility study, twenty patients with end-stage diabetic nephropathy were treated with fractionated total-lymphoid irradiation (TLI, mean dose 25 Gy), before transplantation of a first cadaveric kidney. During radiotherapy, only one patient had a serious side effect (bone marrow depression). After transplantation four patients died (one of a myocardial infarction, one of ketoacidosis, and two of infections occurring during treatment of rejection crises). One graft was lost because of chronic rejection. The other 15 patients have a functioning graft (mean follow-up 24 months) and receive low-dose prednisone alone (less than 10 mg/day, n = 11) or in conjunction with cyclosporine (n = 4) as maintenance immunosuppressive therapy. A favorable clinical outcome after TLI (no, or only one, steroid-sensitive rejection crisis) was significantly correlated with a high pre-TLI helper/suppressor lymphocyte ratio, a short interval between TLI and the time of transplantation, and the occurrence of functional suppressor cells early after TLI. The most striking immunological changes provoked by TLI consisted of a long-term depression of the mixed lymphocyte reaction and of the phytohemagglutinin, and Concanavalin A or pokeweed-mitogen-induced blastogenesis. A rapid and complete recovery of the natural killer cell activity was observed after TLI. A permanent inversion of the OKT4+ (T helper/inducer) over OKT8+ (T suppressor/cytotoxic) lymphocyte ratio was provoked by a decrease of the OTK4+ subpopulation, together with a supranormal recovery of the OKT8+ lymphocytes. A majority of the latter lymphocytes did also express the Leu 7 and the Leu 15 phenotype.

Adult↗
PubMed1987

Anatomy of the major lacrimal gland of rhesus monkeys (Macaca mulatta).

The major lacrimal gland of rhesus monkeys is impalpable within the fatty connective tissue of the upper lateral quadrant of the orbit. Acini of the lacrimal glands are composed of both sparsely and heavily granulated cells that histochemically resemble serous acinar cells of the submandibular salivary gland. The cytoplasmic granules are strongly periodic acid-Schiff (PAS)-positive, and some are also stained by alcian blue for acidic mucosubstances. The lacrimal gland has a simple duct system of intralobular ducts and interlobular excretory ducts. Lymphocytes and plasma cells are common in the periductal stroma. Major lacrimal glands of rhesus monkeys are suitable for comparative and correlative studies of lacrimal and salivary diseases and radiation responses.

Animals↗
PubMed1986

Effect of combined AZQ and radiation on the tolerance of the rat spinal cord.

The effect of combined AZQ (aziridinylbenzoquinone) and ionizing radiation on the rat spinal cord has been investigated. The highest dose of AZQ (3 mg/kg) tolerated by rats weighing 250 g was injected intravenously 15 min before a single dose of radiation or the first of 2 fractional doses. The development of paralysis due to white-matter necrosis in rats of each dose group was scored and dose-response curves were constructed. It has been found that a combination of AZQ with radiation did not lead to a significant shift of the dose-response curve as compared to that of radiation alone. Thus, AZQ administered according to the schedule used in the present study did not seem to reduce the radiation tolerance of the central nervous system.

Animals↗
PubMed1986

Radiotherapy in multiple fractions per day for prostatic carcinoma: late complications.

The late complications associated with two different irradiation schedules with multiple fractions per day (MFD) used for the treatment of prostatic carcinoma are analyzed in 91 patients. There is a relatively high rate of side-effects with fifteen patients (16.5%) developing severe complications due to the radiotherapy. Complications are generally localized in the urinary system and consist mainly of chronic cystitis and incontinence, with only a few exclusive gastro-intestinal problems. The causative factor seems to be pronounced fibrosis of the normal pelvic tissues.

Aged↗
PubMed1986

The combined effect of bleomycin and irradiation on mouse lip mucosa. 1. Influence of timing, sequence and mode of drug administration with single dose irradiation.

The effect of the combination of single dose irradiation and bleomycin on the mucosa of the mouse lip was investigated. Bleomycin was administered either by IP injection or by subcutaneous continuous infusion. With the combined treatment an increased effect was observed compared to irradiation alone. The effect was drug-dose dependent in the range of doses used (5-80 mg/kg) and was similar for both ways of drug administration. There was only a limited influence of timing and sequence of the two agents within a period of 4 days. Since the dose-response curves were shifted in a parallel way, a constant cell killing effect by bleomycin is suggested for all irradiation doses used. This could be due to independent cell kill by the drug, although some mechanism of interaction, such as interference with accumulation of sublethal radiation damage or a true dose modification can not be excluded.

Animals↗
PubMed1986

Target cell and mode of radiation injury in rhesus salivary glands.

Morphological alterations of parotid and submandibular salivary glands of rhesus monkeys were studied 1-72 h and 16-40 weeks postirradiation (PI) with single photon doses of 2.5-15.0 Gy, or 10.2 Gy given in 6 fractions. Acute degeneration and necrosis of serous cells in both parotid and submandibular glands were clearly expressed by 24 h PI and occurred in a dose-related fashion. In submandibular glands, doses of 12.5 or 15.0 Gy damaged mucous cells, but to a considerably lesser extent than the serous cells in the same glands. No significant sparing was evident with dose fractionation. These observations demonstrate the unique sensitivity of serous cells which appear to undergo interphase cell death after irradiation. The results also show that late atrophy was the direct result of acute loss of serous acini and reflects a lack of regeneration of acinar cells receiving acute injury.

Animals↗
PubMed1986

Combinations of single doses and fractionated treatments of cis-dichlorodiammineplatinum (II) and irradiation: effect on mouse lip mucosa.

Tolerance of the lip mucosa of NMRI mice to single and fractionated irradiation combined with cis-diamminedichloroplatinum (II) (cis-DDP) was investigated. For the various combination schedules total drug doses varying from 6 mg kg-1 to 13 mg kg-1 were injected i.p. It was found that cis-DDP did not alter the radiation sensitivity of this tissue at any of the time intervals tested (ranging from 24 h before to 72 h after single dose irradiations). When 5 daily drug injections were given concomitantly with 5 daily radiation treatments, a slight reduction of the lip mucosal reactions occurred, possibly due to partial synchronisation during treatment. No effect was seen when a single injection of cis-DDP preceded two irradiations given with increasing intervals up to 4 h. Both these combined fractionated treatment data suggest no inhibitory effect on repair of sublethal radiation damage. When repeated daily injections of cis-DDP were given in between 2 radiation doses separated by 10 days, no interference with repopulation could be detected. The present study also demonstrated an increase in systemic drug toxicity when cis-DDP was combined with irradiation, compared with that seen with either agent alone.

Animals↗
PubMed1986

Direct analysis of quantal radiation response data.

A direct analysis is proposed for quantal (all-or-nothing) responses to fractionated radiation and endpoint-dilution assays of cell survival. As opposed to two-step methods such as the reciprocal-dose technique, in which ED50 values are first estimated for different fractionation schemes and then fit (as reciprocals) against dose per fraction, all raw data are included in a single maximum-likelihood treatment. The method accommodates variations such as short-interval fractionation regimens designed to determine tissue repair kinetics, tissue response to continuous exposures, and data obtained using endpoint-dilution assays of cell survival after fractionated doses. Monte-Carlo techniques were used to compare the direct and reciprocal-dose methods for analysis of small-scale and large-scale studies of response to fractionated doses. Both methods tended toward biased estimates in the analysis of the small-scale (3 fraction numbers) studies. The alpha/beta ratios showed less scatter when estimated by the direct method. Most important, the 95 per cent confidence intervals determined by the direct method were more appropriate than those determined by reciprocal-dose analysis, for which 18 per cent (small-scale study) or 8 per cent (large-scale study) of the confidence intervals did not include the 'true' value of alpha/beta.

Animals↗
PubMed1986

Acute and late radiation injury in rhesus monkey parotid glands. Evidence of interphase cell death.

Acute and chronic salivary gland dysfunction are common sequelae of radiotherapy for head and neck cancer; but the associated morphologic changes, especially of the acute damage, have received relatively little study. For investigation of the morphologic characteristics of acute radiation injury to parotid glands, rhesus monkeys were studied 1-72 hours after parotid irradiation with single doses of 2.5-15.0 Gy. The acute damage from all doses was clearly expressed by 24 hours. Histologically, parotid glands irradiated with 2.5 or 5.0 Gy had random degeneration and necrosis of the serous acinar cells. Doses of 7.5-15.0 Gy produced widespread degeneration along with necrosis of whole acini. Serous cell damage was accompanied by neutrophilic inflammation that subsided after 24 hours to become replaced by plasma cell and lymphocytic infiltrates. Parotid glands receiving 7.5-15.0 Gy were atrophic at 16-22 weeks after irradiation and showed no recovery by 40 weeks. Although parotid acinar cells are well-differentiated nondividing cells, these observations show that they express lethal radiation injury in interphase within hours of receiving a radiation dose as low as 2.5 Gy. This is unlike most mammalian cells that express radiation injury during mitosis. Chronic atrophy is a consequence of this direct, irreversible, and early injury, rather than the result of radiation-induced changes in the vasculature.

Acute Disease↗
PubMed1986

Unique radiosensitivity of serous cells in rhesus monkey submandibular glands.

The saliva of patients undergoing radiation therapy for head and neck cancer contains increased acidic mucosubstances associated with a reduced serous component. To assess the morphologic features of the acute radiation damage in serous versus mucous acinar cells, the mixed serous/mucous submandibular glands of 18 rhesus monkeys were studied 1-72 hours after irradiation with single doses of 2.5-15.0 Gy. Selective degeneration and necrosis of serous cells was observed with doses of 2.5-7.5 Gy. Doses of 10.0-15.0 Gy caused widespread destruction of whole serous acini, but only isolated mucous cells were affected. The lesions were clearly expressed by 24 hours. Transient exudation of neutrophils was replaced by plasma cells and lymphocytes. Examination at 16, 22 and at 40 weeks revealed that late atrophy was caused solely by loss of serous acini in glands treated with 7.5 and 10.0 Gy. Although both serous and mucous acini were reduced in glands treated with 12.5 and 15.0 Gy, the atrophy was mainly due to loss of serous acini. The finding that serous cells are more vulnerable to radiation injury than mucous cells provides a morphologic explanation for early and late changes in saliva composition after salivary gland irradiation.

Animals↗
PubMed1986

Surgical and microscopic anatomy of parotid and submandibular salivary glands of rhesus monkeys (Macaca mulatta).

Wedge biopsy of the caudal borders of the parotid or submandibular salivary glands of rhesus monkeys avoids major nerves, ducts, and blood vessels. This is a minor surgical procedure that provides adequate material for in vitro studies and causes no significant postoperative complications. Gross and light microscopic anatomy of the rhesus and human salivary glands are similar. We have concluded that rhesus monkeys are good models for human salivary diseases, including radiation sialoadenitis.

Animals↗
PubMed1985

The kinetics and capacity of repair of sublethal damage in mouse lip mucosa during fractionated irradiations.

The kinetics and capacity of repair of sublethal damage in mouse lip mucosa have been investigated. To assess the rate of repair 2 and 5 irradiations have been given with intervals ranging from 1 to 24 hours. It was found that the sublethal damage induced by a dose of approximately 10 Gy was fully recovered in approximately 4 hr. After a dose of 5-6 Gy, cellular repair was completed within 3 hr. The half time of repair (T1/2) was estimated to be approximately 72 min for 10 Gy and approximately 54 min for 5-6 Gy. Although these results suggest that the rate of repair is dependent on the fraction size, the possible influence of the amount of repair of sublethal radiation damage with the various fraction sizes used can not be ruled out. To evaluate the capacity of repair, a single dose, 2, 4 and 10 fractions have been given in a maximal overall time of 3 days in order to minimize the influence of repopulation. The slope of the isoeffective curve was 0.32 and the alpha/beta ratio was 8.5 Gy. This indicates that the capacity of cellular repair of lip mucosa is similar to those of other rapidly proliferating tissues but smaller than those of late responding tissues. The results of the present and other studies demonstrate that there are considerable differences in the repair characteristics between acutely and late responding tissues. These features have to be dealt with when fractionation schedules are markedly altered.

Animals↗