Biomedical subjects

N R Hunter

Publications and source records attributed to N R Hunter.

At least 19 recordsLinked to original sources

PubMed2000

Assessment of resistance to paclitaxel of murine tumors by (99m)Tc-MIBI/(201)Tl dual-radionuclide imaging.

This study investigated P-glycoprotein (Pgp) expression by murine tumors with and without resistance to paclitaxel and the role of (99m)Tc-2-methoxyisobutylisonitrile (MIBI)/(201)Tl imaging in predicting the effect of paclitaxel. Antitumor effect of paclitaxel and biodistribution of the radiopharmaceuticals were evaluated in mice bearing four tumor types. Pgp expression did not correlate with the antitumor efficacy of paclitaxel. Although the absolute uptake of (99m)Tc-MIBI did not correlate with Pgp expression, (99m)Tc-MIBI could predict paclitaxel sensitivity by its higher uptake.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Maximizing therapeutic gain with gemcitabine and fractionated radiation.

PURPOSE/OBJECTIVE: The nucleoside analogue gemcitabine inhibits cellular repair and repopulation, induces apoptosis, causes tumor growth delay, and enhances radiation-induced growth delay. After single doses of drug and radiation, maximum enhancement of tumor response was obtained when gemcitabine preceded radiation by at least 24 h. Conversely, the cellular radioresponse of the normal gastrointestinal epithelium was slightly protected when gemcitabine and radiation were separated by 24 h. This differential response created a time frame within which therapeutic gain could be maximized. In our present investigation, we sought to define the most therapeutically beneficial scheme of gemcitabine administration when combined with fractionated radiotherapy. METHODS AND MATERIALS: C3Hf/Kam mice were given identical drug and radiation schedules of administration, and both normal tissue (jejunal mucosa) and tumor (Sa-NH) responses were measured. Irradiation was given once per day for 5 days in normal tissue and tumor growth delay studies and twice per day for the tumor cure endpoint. A total dose of 25 mg/kg gemcitabine was given i.p. in 1 of 3 schedules: a single dose of 25 mg/kg 24 h before the start of fractionated irradiation, 12.5 mg/kg 24 h before the first and third radiation doses, or 24 h before each of 5 radiation doses. Groups of mice bearing 7- or 8-mm diameter tumors were treated with gemcitabine alone or in combination with fractionated irradiation under ambient or hypoxic conditions. The survival response of the jejunal mucosa was quantified by the microcolony assay and histologically by quantifying apoptosis, mitosis, S-phase fraction, and crypt cellularity. RESULTS: For tumor growth delay, dose-modifying factors (DMFs) were similar (1.34-1.46) for all 3 schedules of drug administration. In contrast, the response of the jejunum was strongly dependent on the schedule of gemcitabine administration. A single dose of gemcitabine before the start of fractionated radiotherapy resulted in slight radioprotection (DMF 0.96). Two doses and 5 daily doses of gemcitabine enhanced radiation response by factors of 1.09 and 1.23, respectively. Major factors affecting the response of the jejunal mucosa were apoptotic death of S-phase cells exposed to gemcitabine and cell cycle synchrony of surviving cells. Tumor reoxygenation was found to be a major mechanism for tumor radioenhancement, in addition to those reported earlier. CONCLUSION: All 3 schedules of drug administration produced therapeutic gain; however, when gemcitabine was given more than once in a 5-fraction radiation treatment schedule, normal tissue toxicity increased. The highest therapeutic gain (1.4) was achieved by giving a single dose of gemcitabine (25 mg/kg) 24 h before the start of fractionated radiotherapy.

Animals↗

PubMed1999

Association of increased radiocurability of murine carcinomas with low constitutive expression of p21(WAF1/CIP1) protein.

PURPOSE: The study investigated whether basal, constitutive levels of p21(WAF1/CIP1) protein in murine carcinomas are related to in vivo tumor radioresponse. The study is based on recent observations demonstrating that in vitro cancer cell lines are resistant to cytotoxic drugs when they express high basal levels of p21(WAF1/CIP1) protein, and that the loss of the p21 gene in the HCT116 human colorectal cancer cell line results in increased radioresponse of xenografts derived from that cell line. METHODS AND MATERIALS: Protein levels of p21(WAF1/CIP1), p53, bax, and bcl-2 were determined in 8 carcinomas (3 mammary carcinomas designated MCa-4, MCa-29, and MCa-35, 2 squamous cell carcinomas designated SCC-IV and SCC-VII, ovarian adenocarcinoma OCa-I, hepatocarcinoma HCa-I, and adenosquamous carcinoma ACa-SG) syngeneic to C3Hf/Kam mice using Western blot analysis. The tumors, growing in the right hind legs of mice, were 8 mm in diameter at the time of analysis. These tumors greatly differ in their radioresponse, assessed by TCD50 assay, and in their susceptibility to radiation-induced apoptosis. RESULTS: Protein levels of these oncogenes varied among tumors, with p21(WAF1/CIP1) showing the greatest variation: its mean densitometric value ranged from 1 to 19. Bcl-2 levels also showed broad variation in densitometric values, from 1 to 10. In comparison, bax and p53 (7 of 8 tumors contained wild-type p53) varied much less among different tumor types; their variation was within a 5-fold range, and the level of p53 was similar in 6 of 8 tumors. Tumor radioresponse correlated significantly (R = 0.77, p = 0.02) only with the magnitude of p21(WAF1/CIP1)expression: tumors with high levels of p21(WAF1/CIP1)were less radiocurable than those with lower levels. Tumor radiocurability showed a significant positive correlation (p = 0.02) with the extent of radiation-induced apoptosis, indicating that tumors that responded to radiation with higher percentages of apoptosis were more curable by radiation. Despite a strong trend to correlation, (p = 0.15), p21(WAF1/CIP1) expression did not correlate significantly with radiation-induced apoptosis, which suggested that p21(WAF1/CIP1) influenced tumor radioresponse by mechanisms beyond that of apoptosis induction. CONCLUSION: Our findings showed that murine tumors exhibit wide variation in constitutive levels of p21(WAF1/CIP1) which had a significant relationship with tumor radioresponse: tumors with high levels of p21(WAF1/CIP1) were less radiocurable than those with lower levels. These findings support the concept that p21(WAF1/CIP1) is a major determinant of tumor radioresponse in vivo, and may have important clinical implications. The pretreatment assessment of p21(WAF1/CIP1) protein could serve as a useful predictor of radiotherapy outcome and may assist in selecting an effective treatment modality.

Animals↗

PubMed1999

[Inhibition of tumor neo-angiogenesis and induction of apoptosis as properties of docetaxel (taxotere)].

Paclitaxel and docetaxel are potent drugs that are effective in the treatment of malignant tumors. The cytotoxic action of these drugs is not fully understood, but it appears to be mediated mainly through mitotic arrest and subsequent apoptosis. Because no information is available on the antiangiogenesis action of docetaxel, the investigations were performed to determine whether inhibition of neoangiogenesis plays a role in docetaxel's antitumor efficacy. Four different mouse tumors, two squamous cell carcinomas (SCC-IV; SCC-VII) and two adenocarcinomas (MCA-4; MCA-29) were assayed for angiogenic activity using the in vivo i.c. angiogenesis assay. Tumor cells (5 x 10(5)) were injected i.c. into the skin flap over the abdominal wall, and the number of new blood vessels at the tumor cell injection site was determined 2, 4, 6, 8, 10 and 12 days later. The mice were treated with docetaxel (Taxotere--31.3 mg/kg i.v.) 1 or 4 days after tumor cell injection. The number of new blood vessels increased with time. Docetaxel reduced the number of newly formed blood vessels in MCAs, but not in SCCs. The reduction was associated with slower tumor growth. In a separate set of experiments we observed that docetaxel's inhibitory effect on the two MCAs was histologically associated with massive tumor cell destruction by means of both apoptosis and necrosis. This was not observed for the two SCCs. Since no reduction in blood vessels occurred in tumors unresponsive to docetaxel, the inhibition of neoangiogenesis in docetaxel-responsive tumors was likely the result of a decrease in angiogenic stimuli due to docetaxel's destruction of tumor cells.

Adenocarcinoma↗

PubMed1999

Antitumor activity of poly(L-glutamic acid)-paclitaxel on syngeneic and xenografted tumors.

Poly(L-glutamic acid)-paclitaxel (PG-TXL) is a new water-soluble paclitaxel derivative that has shown remarkable antitumor activity against both ovarian and breast tumors. The purpose of this study was to test whether the antitumor efficacy of PG-TXL depends on tumor type, as is the case for paclitaxel, and to test whether paclitaxel-resistant tumors could be responsive to PG-TXL. We evaluated the therapeutic activity of PG-TXL against four syngeneic murine tumors (MCa-4, MCa-35, HCa-1, and FSa-II) inoculated i.m. into C3Hf/Kam mice, a human SKOV3ip1 ovarian tumor injected i.p. into nude mice, and a human MDA-MB-435Lung2 breast tumor grown in the mammary fat pad of nude mice. Two paclitaxel-responsive murine tumors, MCa-4 and MCa-35, showed significant growth delay with PG-TXL given as a single i.v. injection at its maximum tolerated dose of 160 mg of equivalent paclitaxel/kg or even at a lower dose of 120 mg of equivalent paclitaxel/kg. The other two murine tumors, HCa-1 and FSa-II, did not respond particularly well to either of the two agents, although significant growth delay was observed for both tumors with PG-TXL. In mice with SKOV3ip1 tumors, the median survival times for mice treated with PG alone and PG-TXL at doses of 60 or 120 mg of equivalent paclitaxel/kg were 43, 61, and 75 days, respectively; no survival difference was found between paclitaxel-treated and Cremophor vehicle-treated mice. In mice with MDA-MB-435Lung2 tumor, PG-TXL at a dose of 120 mg of equivalent paclitaxel/kg produced regression of the tumor in 50% of the animals, and in the remaining mice, micrometastases in the lung were found only in 25% of the animals. In comparison, treatment with paclitaxel at 60 mg/kg did not result in tumor regression, and the rate of lung metastases was 42%. These results clearly demonstrate that PG-TXL has significant therapeutic activity against breast and ovarian tumors tested in this study. Future studies to elucidate the mechanism of action of PG-TXL and to assess its clinical applications are warranted.

Animals↗

PubMed1999

Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas.

The study investigated whether a relationship exists between the extent of epidermal growth factor receptor (EGFR) expression and in vivo radiocurability of murine tumors. EGFR expression was determined in nine carcinomas (four mammary carcinomas, designated MCa-4, MCa-29, MCa-35, and MCa-K; two squamous cell carcinomas, designated SCC-IV and SCC-VII; an ovarian adenocarcinoma, OCa-I; a hepatocarcinoma, HCa-I; and an adenosquamous carcinoma, ACa-SG) syngeneic to C3Hf/Kam mice using Western blot analysis. These tumors greatly differed in their radioresponse, assessed by TCD50 assay, and in their susceptibility to radiation-induced apoptosis. Likewise, the expression of EGFR greatly varied, by as much as 21-fold, and the magnitude of the EGFR expression positively correlated with increased tumor radioresistance. The levels of EGFR inversely correlated with radiation-induced apoptosis, suggesting that the lack of sensitivity to apoptosis induction was a major mechanism responsible for radioresistance of tumors with high EGFR. This correlation was highly significant only for wild-type p53 carcinomas. Radiation activated EGFR autophosphorylation and increased the activity of protein tyrosine kinase, but only in tumors with high EGFR expression. Thus, EGFR expression was a major determinant of tumor radioresponse in vivo. The pretreatment assessment of EGFR expression could predict radiotherapy outcome and may assist in selecting an effective treatment modality.

Animals↗

PubMed1998

The hollow box maxillary obturator.

A case is reported assessing the problems encountered after surgical resection of the maxilla. The use of a hollow box obturator and details of its construction are described. The importance of skin grafting of the maxillary defect and use of available anatomical undercuts to optimise support and retention of the obturator is stressed. By provision of a lightweight hollow obturator, the weight of the prosthesis is kept to a minimum, helping retention, and allowing good resonance during speech. Initially the patient was to be assessed for an implant retained prosthesis, however, a satisfactory conventional prosthesis met the functional and aesthetic needs of the patient and avoided the need for further surgery for placement of implants.

Denture Design↗

PubMed1997

Enhanced radioresponse of paclitaxel-sensitive and -resistant tumours in vivo.

Paclitaxel is a potent chemotherapeutic drug and also has the potential to act as a radioenhancing agent. The latter is based on its ability to arrest cells in the radiosensitive G2M phases of the cell cycle; the weight of supporting evidence is derived mainly from in vitro studies. Our previous in vivo experiments identified enhanced tumour radioresponse predominantly attributable to tumour reoxygenation occurring as a result of paclitaxel-induced apoptosis. The current study investigated whether paclitaxel enhanced the radioresponse of tumours which are insensitive to apoptosis induction, but exhibited mitotic arrest, and compared the degree and kinetics of the response to that in tumours which develop apoptosis. The mouse mammary carcinoma MCa-29 (apoptosis sensitive) and the squamous cell carcinoma SCC-VII (apoptosis resistant) were used. In addition, the study investigated whether paclitaxel affected normal skin radioresponse to determine if a therapeutic gain could be achieved. Paclitaxel enhanced the radioresponse of both types of tumours. In the SCC-VII tumour, radiopotentiation occurred within 12 h of paclitaxel administration coincident with mitotic arrest, where enhancement factors (EFs) ranged from 1.15 to 1.37. In MCa-29 tumour, the effect was greater, EFs ranging from 1.59 to 1.91 and occurred between 24 and 72 h after paclitaxel when apoptosis was the predominant microscopic feature of treated tumours and when tumour oxygenation was found to be increased. The acute skin radioresponse and late leg contracture response were essentially unaffected by prior treatment with paclitaxel. Therefore, by two distinct mechanisms, paclitaxel was able to enhance the radioresponse of paclitaxel-sensitive and -resistant tumours, but not the normal tissue radioresponse, thus providing true therapeutic gain.

Animals↗

PubMed1997

Potentiation of antitumor efficacy of paclitaxel by recombinant tumor necrosis factor-alpha.

We studied the combination of tumor necrosis factor (TNF) and paclitaxel. Our aim was to determine whether TNF increases the antitumor efficacy of paclitaxel and if so whether the increase is mediated through the enhancement of apoptosis induction by paclitaxel. Mice bearing 6 mm MCa-K or MCa-4 mammary carcinomas, OCa-I ovarian carcinomas, or HCa-I hepatocarcinomas in their legs were treated with TNF, paclitaxel of their combination. TNF was administered i.p. daily at a dose of 10 micrograms per mouse for 7 days; paclitaxel at a dose of 40 mg/kg per mouse was given as a single i.v. injection 1 h before the second dose of TNF. Tumor growth delay was used as the endpoint of tumor response to the treatments. The results showed that the combination was either additive or supraadditive; supraadditive action occurred in three of the four tumors tested. The enhancement factors (EFs) were 1.24 for MCa-K, 1.53 for MCa-4, 1.0 for OCa-I and 2.17 for HCa-I. Histological analysis of treated MCa-K tumors revealed that TNF alone did not induce apoptosis of tumor cells, but in the combination it enhanced the apoptotic response to paclitaxel. Thus, TNF increased the antitumor efficacy of paclitaxel by enhancing cellular sensitivity to paclitaxel's induction of apoptosis. The results imply that the combination of TNF and paclitaxel has potential as a treatment for cancer.

Animals↗

PubMed1997

The effect of tumor size on necrosis and polarographically measured pO2.

Tumor necrosis and oxygen status were investigated as a function of tumor size in three syngeneic murine carcinomas, MCa-4, OCa-I, and SCC-VII, in C3Hf/Kam mice. Tumor necrosis was estimated histologically, and tumor oxygenation determined by direct polarographic histography. As tumor volume increased necrosis increased significantly in all three tumor types (p < 0.001). Similarly, as tumor volume increased from 200 to 1400 mm3, hypoxia, defined as the percentage of measured pO2 values < or = 5.0 mm Hg, increased from 55.1% to 95.9%, 70.3% to 81.4%, and 56.8% to 98.5% in MCa-4, OCa-I, and SCC-VII tumors respectively (p < 0.001). Correcting pO2 for necrosis reduced the tumor size dependence of measured tumor hypoxia in all three tumor types but in no case was the reduction significant. The main effect of correction was to shift the fitted curves of percent pO2 values < or = 5.0 mm Hg down toward lower percentages for all tumors. This change was significant for MCa-4 and OCa-1 tumors (p < 0.001), but not for SCC-VII (p = 0.054). Defining the influence of variables such as necrosis that affect polarographic assessment of tumor oxygenation is important to enhance the technique's reliability and prospect as an investigative and predictive tool.

Animals↗

PubMed1997

Synthesis, biodistribution and imaging properties of indium-111-DTPA-paclitaxel in mice bearing mammary tumors.

UNLABELLED: Paclitaxel, an antineoplastic agent that stabilizes microtubules and arrests cells in the G2/M cell cycle phase, has shown activity against many common cancers, including ovarian and breast tumors. In order to evaluate the potential value of radiolabeled paclitaxel as an imaging tool in tumors, we synthesized 111In-DEPA-paclitaxel and investigated its biodistribution and gamma scintigraphic imaging properties. METHODS: Mice bearing a paclitaxel-responsive mammary tumor (MCA-4) were used. DTPA-paclitaxel was labeled with 111In with a radiochemical yield of 84% and radiochemical purity of 90%. Each mouse received 5 microCi of radiotracers intravenously for biodistribution studies and 100 microCi for gamma scintigraphic studies. Indium-111-DTPA was used as a control. RESULTS: In tumor-bearing mice, 111In-DTPA was characterized by rapid clearance from the plasma with negligible retention in the tumor, the liver and other body parts. In contrast, 111In-DTPA-paclitaxel exhibited a pharmacological profile resembling that of paclitaxel. Furthermore, a significant uptake of 111In-DTPA-paclitaxel was observed in the tumor. The tumor-to-muscle ratios were 2.64, 3.16 and 6.94 at 30 min, 2 hr and 24 hr, respectively, although absolute uptake in the tumor decreased from 1.95% (injected dose/g) at 30 min to 0.21% at 24 hr after injection. The tumor-to-blood ratio reached 50 at 24 hr after injection. Gamma scintigraphy and autoradiographic studies clearly showed the retention of radiolabeled paclitaxel in the tumor 24 hr after injection. CONCLUSION: These studies suggest that 111In-DTPA-paclitaxel may be clinically useful in studying the uptake of paclitaxel in solid tumors.

Animals↗

PubMed1997

Docetaxel enhances tumor radioresponse in vivo.

Although the radiosensitizing potential of paclitaxel has been investigated extensively in cancer treatment, a sister taxane, docetaxel, has been studied rarely. We investigated the ability of docetaxel to enhance in vivo tumor radioresponse and influence radiation injury to normal tissue. In addition, mitotic arrest and apoptosis in tumors and normal tissues were assessed after docetaxel administration to determine whether these cellular effects underly its radio-modifying action. Mice bearing in their legs 8-mm isotransplants of a murine mammary carcinoma, designated MCA-4, were treated with 33 mg/kg docetaxel i.v., 9-21 Gy single-dose local tumor irradiation, or both (in which case radiation was given 9 or 48 h after docetaxel). Tumor growth delay was the end point of the treatments. Mitotic arrest and apoptosis were assayed 1-72 h after treatment with docetaxel. Normal tissue radioresponse was determined using jejunal crypt cell survival 3.5 days after mice were exposed to 9.2-14.8 Gy single-dose, total-body irradiation; the mice were treated with 33 mg/kg docetaxel i.v. 3, 9, or 48 h before irradiation. Docetaxel was assessed for its ability to induce mitotic arrest and apoptosis in jejunum 1-72 h after treatment. Docetaxel induced both mitotic arrest and apoptosis in both tumor and jejunum. Mitotic arrest preceded apoptosis and peaked in the tumor at 9-12 h after treatment; it peaked at 3 h in jejunum. Docetaxel enhanced tumor radioresponse by a factor of 1.45 when the drug was given 9 h before radiation and 2.33 when it was given 48 h before. In contrast, it only slightly enhanced radiation-induced damage of the jejunum and only when given 3 or 9 h before irradiation. Thus, docetaxel given within 2 days before irradiation acted as a potent enhancer of tumor radioresponse and increased the therapeutic gain of irradiation.

Animals↗

PubMed1996

Relationship of mitotic arrest and apoptosis to antitumor effect of paclitaxel.

BACKGROUND: Microtubules are cellular organelles with functions that include control of cell division by mitosis, cell morphology, and transport of material within the cell. The anticancer drug paclitaxel (Taxol) promotes accelerated assembly of excessively stable microtubules. Consequently, treated cells tend to become arrested in mitosis. The drug also induces apoptotic cell death in vitro and in vivo. Prior to this study, the relative contributions of mitotic arrest and apoptosis to the in vivo antitumor effect and the relationship between the two factors had not been established; moreover, it is not known whether paclitaxel-induced mitotic arrest inevitably results in cell death. PURPOSE: Our aim was to quantify the mitotic arrest and apoptosis induced by paclitaxel in 16 murine tumors in vivo and to correlate these two factors with the drug's antitumor effect. METHODS: Inbred C3Hf/Kam mice were implanted with one of the following 16 syngeneic tumors: seven adenocarcinomas (MCa-4, MCa-29, MCa-35, MCa-K, OCa-I, ACa-SG, and HCa-I), two squamous cell carcinomas (SCC-IV and SCC-VII), six sarcomas (FSa, FSa-II, Sa-IIa, Sa-NH, NFSa, and Sa-4020), and one lymphoma (Ly-TH). The tumor growth delay induced by paclitaxel (40 mg/kg body weight given intravenously) was measured in 163 control and 163 treated mice, and its significance was assessed by Student's t test. In a separate group of 439 mice, the percentage of cells in mitosis or apoptosis was scored micromorphometrically at various times after paclitaxel administration. The significance of correlations between paclitaxel-induced tumor growth delay and paclitaxel-induced levels of mitosis or apoptosis was determined by simple correlation and Spearman's rank correlation. P values reported represent two-sided tests of statistical significance. RESULTS: Statistically significant tumor growth delays were found in response to paclitaxel treatment of mice for three of four murine mammary carcinomas (all P < or = .010), an ovarian carcinoma (P = .00003), a salivary gland adenocarcinoma (P = .0002), a lymphoma (P = .0002), and two of six sarcomas (both P < or = .034), but not for either of two squamous cell carcinomas or for the hepatocellular carcinoma. Paclitaxel-induced mitotic arrest was apparent in all tumor types, but to various degrees, and was not significantly correlated with growth delay (R2 = .16; P = .124). In contrast, apoptotic cell death in response to paclitaxel was not ubiquitous, but it was strongly correlated with growth delay (R2 = .59; P = .001). The pretreatment level of apoptosis was correlated with both paclitaxel-induced apoptosis (R2 = .71; P = .00004) and tumor growth delay (R2 = .55; P = .001). CONCLUSION: The antitumor effect of paclitaxel was correlated with paclitaxel-induced apoptosis and base-line apoptosis, but not with mitotic arrest. IMPLICATIONS: Apoptosis is an important mechanism of cell death in response to paclitaxel treatment of in vivo murine tumors. An underlying tumor type-specific propensity for apoptosis is implied by the correlation between pretreatment and paclitaxel-induced apoptosis. Both the extent of pretreatment apoptosis and the paclitaxel-induced percentage of apoptosis may be useful predictors of response to the drug.

Adenocarcinoma↗

PubMed1996

Synthesis and evaluation of water-soluble polyethylene glycol-paclitaxel conjugate as a paclitaxel prodrug.

Water-soluble paclitaxel may cause less side effects and be less costly to administer in comparison to a taxol formulation using a cremophor EL/alcohol vehicle. In this study, polyethylene glycol (PEG; MW 5000) was conjugated to the 2' position of paclitaxel through a spacer succinyl group. PEG-paclitaxel as a non-ionic paclitaxel prodrug was highly water soluble (> 20 mg equiv. paclitaxel/ml). The release of paclitaxel from phosphate-buffered solution was pH dependent. The half-life of PEG-paclitaxel was 7.6, 54 and 311 min at pH 9.0, 7.4 and 6.0, respectively. PEG-paclitaxel inhibited the growth of B16 melanoma cells to an extent similar to that of paclitaxel. In MCA-4 mammary tumor-bearing mice, a single dose of PEG-paclitaxel (40 mg equiv. paclitaxel/kg body weight) significantly delayed tumor growth. The average number of days for the tumor to reach 12 from 8 mm in diameter increased from 6.5 days for control animals to 8.5 days for PEG-paclitaxel-treated animals and 9.4 days for paclitaxel-treated animals. These studies demonstrated that PEG may be used as an effective solubilizing carrier for paclitaxel.

Animals↗

PubMed1996

Improvement in the therapeutic ratio of radiotherapy for a murine sarcoma by indomethacin plus fludarabine.

Fludarabine, an effective repair inhibitor of radiation-induced chromosome breaks, and indomethacin, an inhibitor of prostaglandin synthesis, were shown previously to improve the therapeutic ratio of radiotherapy for murine tumors. The purpose of this study was to determine whether the combination of these two radiosensitizers with different mechanisms of action could further increase the therapeutic ratio of radiotherapy in an FSA mouse sarcoma after single and fractionated irradiation. The effect of the combined treatment on tumors was assessed by the local tumor control assay (TCD50) in mice bearing an FSA sarcoma in the leg. The effect of the combination on normal tissues was assessed by skin desquamation, hair loss and leg contracture in the legs of non-tumor-bearing mice. For the TCD50 assay, after single irradiation, the radiation dose modification factor (DMF) reached 1.2 for both indomethacin (35 micrograms/ml in the drinking water for 10 days) and fludarabine (800 mg/kg intraperitoneally 3 h prior to irradiation). For both drugs combined, the DMF increased to 1.7. No significant increase in normal tissue toxicity was observed with any of the combinations. After fractionated irradiation (16 fractions over 4 days), the DMFs for local tumor control reached 1.3 for indomethacin and 1.8 for fludarabine darabine (400 mg/kg every day for 4 days). The combination of both drugs produced a DMF of 2.0. None of the combinations altered the effects of radiation on skin desquamation, hair loss or leg contracture significantly. The present study suggests that the therapeutic ratio of radiotherapy for a murine sarcoma can be improved by the combination of indomethacin and fludarabine, two agents differing in their mechanisms of radiopotentiation.

Animals↗

PubMed1995

Sequence-dependent antitumor activity of paclitaxel (taxol) and cisplatin in vivo.

The established antitumor efficacy of paclitaxel and cisplatin as single agents and their distinctly different mechanisms of action have prompted laboratory and clinical research into their use in combination. Our in vivo study was performed to investigate the importance of sequence of administration and inter-agent interval. C3Hf/Kam mice bearing OCa-I tumors received paclitaxel and cisplatin. The antitumor efficacy of the combination, measured as re-growth delay and expressed as the enhancement factor (EF), was determined for inter-agent intervals of 1, 9, 24, 48 and 72 hr. Morphometric analysis was used to determine the contribution of induced apoptosis. Our findings showed an additive effect when cisplatin preceded paclitaxel by 1 and 24 hr, producing EF of 1.1 and 1.0, respectively, and a greater than additive effect for 9 and 48 hr, producing EF of 1.3 and 1.8, respectively. This sequence, however, was associated with significant morbidity and mortality. When paclitaxel preceded cisplatin the effect was greater than additive with the EF for 1, 9 and 24 hr, being 1.2, 1.5 and 1.5, respectively, and increasing to a maximum of 1.9 at 48 hr. Thus, for this combination, the therapeutic ratio was improved when paclitaxel preceded cisplatin and was greatest when a 48 hr interval was allowed between drugs. We were unable to attribute the efficacy of the drug combination to increased induction of apoptosis and suggest other possible mechanisms.

Animals↗

PubMed1995

Role of reoxygenation in induction of enhancement of tumor radioresponse by paclitaxel.

We reported previously (L. Milas et al., Cancer Res., 54: 3506-3510, 1994) that paclitaxel greatly enhances the response of a murine mammary carcinoma to subsequent irradiation and hypothesized that the enhanced radioresponse was mediated by tumor cell reoxygenation caused by treatment with paclitaxel. Because paclitaxel induced massive tumor cell destruction by apoptosis, it was reasoned that as apoptotic cells were removed from the tumor more hypoxic cells would have access to oxygen, be reoxygenated, and, thus, become more sensitive to radiation. The present study tested this hypothesis by assessing the effect of 60 or 40 mg/kg paclitaxel on radioresponse of an 8-mm MCA-4 tumor irradiated under air-breathing or hypoxic conditions 9, 24, 48, or 72 h after paclitaxel administration. If the hypothesis was correct, paclitaxel would enhance tumor radioresponse more under air breathing than under hypoxic conditions, and the enhancement would increase as the time between paclitaxel administration and tumor irradiation increased within a few days after paclitaxel treatment but only when radiation was given under air-breathing conditions. The effect of the treatments was determined by tumor growth delay and the radiation dose required to control 50% of the tumors (TCD50). Paclitaxel greatly enhanced tumor radioresponse under air-breathing (and not hypoxic) conditions, increasing tumor growth delay, and reducing TCD50. These effects increased as the time interval between paclitaxel administration and tumor irradiation increased within the observation period of 72 h after paclitaxel treatment. The enhancement factors for tumor growth delay ranged from 1.19 at 9 h to 1.86 at 48 h and for TCD50, from 1.16 at 9 h to 1.47 at 72 h after paclitaxel. Direct measurements of tumor pO2 showed a median value in untreated tumors of 6.2 mmHg, which increased to 10.5 mmHg at 24 h and to 31.2 mmHg at 48 h after paclitaxel administration. Overall, these results show that paclitaxel is a potent enhancer of tumor radioresponse and that its effect is mediated by reoxygenation of hypoxic tumor cells.

Animals↗

PubMed1995

Kinetics of cisplatin-induced apoptosis in murine mammary and ovarian adenocarcinomas.

There is mounting evidence to indicate that the mode of cell death known as apoptosis plays an important role in cancer therapy. Most supporting observations have come from experiments conducted in vitro, and it is important to extend such studies to in vivo systems. We have therefore evaluated the magnitude and kinetics of apoptosis induction in tumors from mice treated with cisplatin (CP). Two transplantable murine tumors were studied: a mammary adenocarcinoma, MCa-4, and an ovarian adenocarcinoma, OCa-1. Tumor-bearing mice were injected with various doses of CP, and specimens were obtained over several days. Apoptosis was scored by morphometric analysis of histological sections of the tumors using the features characteristic of cells undergoing this mode of cell death. The results showed a significant apoptotic response in both tumors within a few hours after injection of the drug. The kinetics were very broad, with apoptotic cells present over essentially the entire time course studied. Dose-response relationships for CP-induced apoptosis were compared to the tumor response measured in terms of tumor growth delay.

Adenocarcinoma↗