|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology Phase I Clinical Trial of Oral COL-3, a Matrix Metalloproteinase Inhibitor, in Patients With Refractory Metastatic CancerFrom the Medicine Branch, Division of Clinical Sciences; Biostatistics and Data Management Section; Investigational Drug Branch, Cancer Therapy Evaluation Program; and Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD. Address reprint requests to William D. Figg, MD, National Cancer Institute, Building 10, Room 5A01, 9000 Rockville Pike, Bethesda, MD 20892; email wdfigg{at}helix.nih.gov
PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.
MATRIX metalloproteinases (MMPs) are a class of enzymes involved in the degradation of the extracellular matrix (ie, gelatinases, collagenases).1 MMPs are implicated in tumor invasion and metastases. Synthetic MMP inhibitors are being developed for their potential therapeutic use in cancer because of demonstrated preclinical antimetastatic and antiangiogenic properties.2 Tetracycline and its derivatives inhibit collagenase activity in a range of cell types.3-6 The proposed mechanisms of action for tetracycline and its derivatives are pleiotropic and include MMP inhibition caused by divalent cation chelation of zinc at the active site of the MMPs, downregulation of the production of the proenzyme, inhibition of the oxidative activation of the proenzyme, and an increase in the degradation of the proenzyme.7-11 By modifying the basic tetracycline structure to produce COL-3, the antimicrobial properties of the molecule were eliminated, whereas the MMP inhibitory properties were retained.7 COL-3, 6-demethyl-6-deoxy-4-dedimethylaminotetracycline, induces potent MMP inhibition of the 2 and 9 isozymes in C8161 cells and human neonatal foreskin fibroblasts conditioned media (Fig 1).12,13 Seftor et al12 demonstrated that COL-3 is a competitive inhibitor of MMP-2. The growth-inhibitory nature of COL-3 has been demonstrated against BPH-1, DU-145, PC-3, and FHS-733 cell lines.14 In vitro, COL-3 also inhibits activity of phospholipase A2,15 inhibits inducible nitric oxide synthase and nitric oxide production,16 and induces apoptosis in several tumor cell lines.14,17
Because of its interesting mechanism of action and potent preclinical activity, COL-3 was entered into clinical phase I testing. The primary end points of this study were to determine the maximum-tolerated dose (MTD) of COL-3 and to document the acute and chronic side-effect profiles. We also sought to determine the pharmacokinetics of COL-3 and the effect of COL-3 on circulating MMP-2, MMP-9, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF).
Patient Enrollment All patients were required to have a documented malignancy that was a solid tumor or lymphoma and were required to have failed to respond to therapy of proven efficacy for their disease. One patient was entered onto this study who had not received any prior therapy (hemangioendothelioma diffusely involving both lungs; Fig 2). Clinically progressive disease was documented by two consecutively rising tumor marker levels (prostate cancer only), at least one new metastatic deposit on technetium-99 bone scintigraphy, progressive soft tissue metastases as measured by radiographic means, or development of a new area of malignant disease. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 and a life expectancy of more than 3 months. Patients were excluded if they were receiving active therapy for their cancer. Women were excluded if they were pregnant or lactating.
All patients were staged within 4 weeks of starting therapy by the use of technetium-99 bone scintigraphy, computed tomography (CT) scan, or other diagnostic imaging method. A baseline chest x-ray and an EKG were obtained at least 2 weeks before starting COL-3. Baseline laboratory studies were obtained within 7 days before starting therapy. Follow-up laboratory studies were obtained at each clinic visit. CT scans and bone scans were repeated approximately every 2 months. Complete response was defined as complete disappearance of all tumor lesions for at least two measurement periods separated by 4 or more weeks; soft tissue abnormalities had to be rebiopsied to document absence of disease, and the lymphangitic spread and/or effusions had to have cleared completely. Partial response was defined as a decrease of 50% or more in the sum of the products of the longest perpendicular diameters of all measurable lesions or a reduction by 50% or more of the number of areas showing, on bone scan, abnormal uptake for longer than 1 month. Progressive disease was defined as a more than 25% increase in the sum of the products of the longest perpendicular diameters of all measurable lesions or the appearance of new lesions. Stable disease was defined as neither responding nor progressing disease for at least 6 months after starting therapy. Patients were removed from the study for progressive disease or unacceptable toxicity. All patients who received any drug were assessable for toxicity. All patients who received 28 days of therapy were assessable for disease response. Toxicity was graded by the National Cancer Institute’s common toxicity criteria, version 1.0. Dose-limiting toxicity (DLT) was defined as a grade 3 or higher nonhematologic or a grade 4 or higher hematologic toxicity within the first 28 days of daily dosing, occurring in at least two of six patients. MTD was defined as one dose level below that dose level at which DLT was seen. The clinical protocol was reviewed and approved by the National Cancer Institute’s institutional review board. Written informed consent was obtained from each patient before he or she participated in the study.
Drug Administration
Pharmacokinetics
Plasma MMP levels
Serum VEGF and bFGF levels
Study Design When the accelerated phase ends, the dose assignment for the first course of a new patient is made in the standard fashion. In this situation, the current dose level is expanded to the standard three to six patients used in a conventional dose-escalation scheme, and the modified Fibonacci method of determining subsequent dose levels is applied from that point forward. DLT was defined as indicated above.
Statistical Analysis Circulating levels of MMP-2, MMP-9, VEGF, and bFGF were examined for association with drug levels in several ways. For each patient, a linear regression line was calculated by using the natural log of the parameter as the dependent variable and cumulative dose of COL-3 as the independent variable. The Wilcoxon signed rank test was used to determine whether the estimated slope coefficients were equal to zero by using all data from the 35 patients. Although for some patients graphical analysis indicated that the relationship between the dependent variable and cumulative drug dose may be curvilinear, the nonlinear terms of the model were determined to be the result of outlier data observations, and thus only the simple linear slope coefficients and intercepts were retained in the model for this analysis. The estimated slope coefficients were also compared according to response category (stable disease, progressive disease, and toxicity) by the Kruskal-Wallis test. In addition, values of the four parameters (MMP-2, MMP-9, VEGF, and bFGF) were evaluated on the difference and percentage difference from baseline by linear regression, as described above. Three patients were considered not assessable for response and were not included in this analysis. The Wilcoxon signed rank test was used to test whether these slopes were equal to zero. The Kruskal-Wallis test was used to test whether the slopes differed according to response category. The differences among the four parameters at baseline and at 28 ± 5 days were also tested to determine whether the changes were equal to zero via the Wilcoxon signed rank test. Finally, the Kruskal-Wallis test was used to determine whether the differences from baseline varied significantly according to response category. In this latter analysis, nine patients were not analyzed because they had not received 28 days of COL-3. All P values are two-sided and were not adjusted for the number of parameters evaluated. As such, they should only be interpreted as exploratory. Confirmation would be required to more firmly establish the significance of the relationship identified in this study.
Patient Characteristics Thirty-five patients with advanced refractory metastatic cancer were enrolled onto this study (Tables 1 and 2). The median height, weight, and body surface area were 172.2 cm, 81.0 kg, and 1.93 m2, respectively. Thirty of 35 patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. Thirty-four (97%) of 35 patients had received at least one prior therapy for their cancer. There was no prior treatment for one patient with hemangioendothelioma (Fig 2). The two most frequent tumor types were prostate cancer (n = 7) and colon cancer (n = 7).
Clinical Outcomes At the first dose level, grade 2 phototoxicity was observed and the trial was immediately converted to use a modified Fibonacci schema and a standard dose-escalation schema. Based on the toxicities noted in the first two patients, more than three patients were accrued on each dose level. Mandatory routine use of sunblock with a sun protection factor (SPF) of 28 was implemented with dose level 2. The sunblock used contained micronized titanium dioxide, which protects against ultraviolet (UV) A and UVB. In addition, we recommended sun avoidance and covering sun-exposed areas with clothing. Twenty-one patients were removed from the study for progressive disease, 10 were removed for toxicity, and three were not assessable. One patient was still receiving therapy at the time of this writing. Eight patients remained on-study for more than 60 days. Thirteen patients were taken off-study within 30 days, and 14 patients were taken off-study between 31 and 60 days. Eight patients had stable disease by CT scan at the first 2-month follow-up and continued on-study for more than 61 days. One patient with hemangioendothelioma experienced disease stabilization for 26+ months and remains on-study. Seven patients had tumor histology of nonepithelial origin (Table 2). Three of these seven patients had disease stabilization for more than 6 months; these included three women with hemangioendothelioma, metastatic Sertoli-Leydig cell tumor of the ovary, and fibrosarcoma metastatic to the lung.
Toxicities COL-3 was well tolerated at the lower doses (36, 50, and 70 mg/m2 orally daily) during treatment except for cutaneous phototoxicity. At the highest dose (98 mg/m2/d), all patients who continued to receive COL-3 for at least 2 weeks developed sunburns despite sun avoidance, wearing protective clothing, and daily use of sunblock. Cutaneous phototoxicity was therefore dose limiting at the dose of 98 mg/m2/d. However, some degree of photosensitivity occurred in 69% of all patients. Ten patients experienced toxicity that necessitated the discontinuance of COL-3. These patients were grouped together in our molecular correlative assessments (see below). Cutaneous phototoxicity presented as a sunburn-like eruption confined to sun-exposed skin. This was graded as follows: grade 1, erythema; grade 2, erythema and pain; grade 3, erythema, blisters, and pain; and grade 4, sloughing of the skin. At dosage levels 1, 2, 3, and 4, four (57%) of seven, two (50%) of four, 11 (73%) of 15, and seven (78%) of nine patients, respectively, experienced phototoxicity. At dosage level 2, the mandatory use of sunblock was implemented. The erythema would resolve with time, while the patient continued to receive COL-3 at dose levels 1, 2, and 3. Several patients developed phototoxicity while driving in a car, indicating that sunburn occurred through window glass. Patients who were compliant with sunblock usage and other sun-protection procedures did not develop as severe erythema as those who did not. At each dosage level, there was one African-American individual. The only African-American who experienced sunburn received 98 mg/m2/d. Non–dose-related toxicities included anemia, anorexia, constipation, dizziness, elevated liver function test results, fatigue, fever, headache, heartburn, nausea, vomiting, neurotoxicities, and three cases of drug-induced lupus (Table 3). Eight patients had drops in their hemoglobin levels while receiving COL-3. Two of eight patients were anemic when enrolled and the anemia worsened while they were receiving COL-3. Six of eight patients had drops in their hemoglobin levels that were not fully explained. One patient had occult blood detected in his stool and therefore could have had significant gastrointestinal blood loss, although documentation was not obtained. A second patient had anemia (hemoglobin level, 7.8 to 6.1 g/dL) during a period of major fluid shifts, possibly related to a dilutional effect. Four of eight patients had unexplained drops in their hemoglobin levels (drops of 3.4 to 5.2 g/dL) during 1 to 2 months of COL-3 treatment. No leukopenia or thrombocytopenia was observed in any of these four cases. Three of these patients had bone marrow examinations that revealed ringed sideroblasts (Rudek et al, manuscript in preparation). One individual was rechallenged with COL-3 and developed anemia a second time. In this last individual, follow-up was extended until the anemia resolved. A bone marrow biopsy obtained at this time showed no evidence of ringed sideroblasts. Therefore, in this patient, the bone marrow abnormality resolved along with the reversal of the anemia.
Three patients developed drug-induced systemic lupus erythematosus (SLE) and presented with arthralgia and fevers. These patients did not have a personal or family history of SLE. Two patients had prostate cancer and one had colon cancer. SLE was confirmed with laboratory studies such as antinuclear antibody and antihistone elevations.2 COL-3 was discontinued in these patients because of the SLE. Two of the patients required systemic treatment with corticosteroids to alleviate the symptoms.
Pharmacokinetics
The median single-dose half-life was 56.1 hours and ranged from 13.6 to 144.4 hours. The median apparent total clearance of COL-3 and pseudo–steady-state apparent volume of distribution were 0.01 L/h/kg and 0.64 L/kg, respectively. Patient no. 9 was excluded from this analysis because his pharmacokinetic data were likely influenced by milk of magnesia usage. The Jonckheere-Terpstra trend test revealed that there was a significant association between dose category and Cmax (P = .001) (Fig 3). An analysis performed after examination of the data indicated that the Cmax levels in the 70- and 98-mg/m2 dose categories were not significantly different (P = .77, Wilcoxon rank sum test). The Jonckheere-Terpstra trend test also revealed a potentially significant association between dose category and T1/2 (P = .007) and VdPSS/F (P = .008). Spearman rank correlation analysis indicated that these same parameters were also moderately well correlated with actual dose (mg/kg): Cmax, r = .60 (P = .0002); T1/2, r = .52 (P = .002); and VdPSS/F, r = .54 (P = .001).
Plasma MMP Levels Changes in MMP-2 and MMP-9 were examined in several ways for significant effects. Linear regression analysis plotted the natural log of MMP-2 and MMP-9 values as dependent variables against cumulative dose. Slopes of the lines obtained from each patient did not differ significantly from zero (P = .29 and P = .75 for MMP-2 and MMP-9, respectively). The Kruskal-Wallis test identified a possible relationship between MMP-2 and cumulative dose (P = .042). Patients with progressive disease had a slight tendency for increased natural log of MMP-2 with increasing cumulative dose. Negative slopes were observed in patients with stable disease or toxicity. A box and whisker plot (Fig 4) summarizes the slope estimates of the natural log of MMP-2 levels versus cumulative dose for each patient; positive data points represent positive slopes and negative data points represent negative slopes.
Tests for whether slopes were equal to zero or differed according to response category with respect to the absolute difference from baseline did not indicate statistically significant effects for either MMP-2 (P = .90 and P = .065, respectively) or MMP-9 (P = .75 and P = .42, respectively). For the percentage difference from baseline, the same tests failed to identify significant effects for either MMP-2 (P = .92 and P = .071, respectively) or MMP-9 (P = .92 and P = .40, respectively). Finally, tests to evaluate change from pretreatment values to day 28 ± 5 indicated no statistical significance, whether tested for slopes equal to zero (P = .36 for MMP-2 and P = .14 for MMP-9) or for equality of slopes according to response category (P = .17 for MMP-2 and P = .91 for MMP-9) (data not shown).
Serum VEGF and bFGF Levels
COL-3 is a novel MMP inhibitor with potent preclinical antimatrix metalloproteinase activity. With sun avoidance, protective clothing, and the prophylactic use of sunblock, the MTD of COL-3 in this study was 70 mg/m2/d. The dose of 36 mg/m2/d was consistently well tolerated without sunblock. The most concerning toxicities seen in this study were the high rate of phototoxicity, three cases of drug-induced SLE, and several cases of anemia. Several patients with progressive disease before study continued to receive COL-3 for long periods. One patient has had disease stabilization for 26+ months. This patient had not received prior cytotoxic chemotherapy. Perhaps this suggests that MMP inhibitors should be implemented early in the course of treatment, as has been recommended by Folkman et al22 for all antiangiogenesis agents. Of seven patients with tumors of nonepithelial origin, three showed some degree of clinical benefit from COL-3. Because three (43%) of seven such patients showed benefit in a phase I study, a phase II study in a similar cohort of patients seems reasonable. The therapeutic effect of COL-3 may also be more evident in less heavily pretreated patients, which is fully appropriate in such a patient subset (nonepithelial origin). Because COL-3 has a pleiotropic antiangiogenic effect, it may have a wider application than traditional MMP inhibitors that just inhibit selected MMPs. We recommend the dose of 36 mg/m2/d for future studies that use COL-3 because this dose was well tolerated. Nonetheless, 57% of patients developed photosensitivity without the diligent use of sunblock. However, a dose of 70 mg/m2/d may be considered if diligent sun precautions are used. The patterns observed for MMP-2 plasma levels in this study are compatible with those anticipated for an MMP inhibitor that downregulates their expression and would require confirmation to establish their validity. Figure 4 summarizes the changes in the slope of the MMP-2 versus cumulative dose line for each patient with regard to the response category (progressive disease, stable disease, or toxicity). For patients with progressive disease as their best response, MMP-2 levels generally tended to increase over time, thereby suggesting an aggressive phenotype in those individuals. In three patients with disease stabilization, MMP-2 levels decreased slightly over time, thereby suggesting inhibition of the production of MMP-2 protein. It is not clear whether inhibition of protein production was effected through inhibition of MMP-2 transcription, translation, or the release of MMP-2 protein from the respective cells. It is also not clear whether this MMP-2 production was from vascular endothelial cells, tumor cells, or both. MMP-2 levels decreased with increasing cumulative dose of COL-3 in many of the patients with drug-induced toxicity to a greater degree than the reduction seen in patients with stable disease. The reason for this association is also not clear. The increased sensitivity to the sun seen in this trial is a classic phototoxic reaction, wherein subjects exposed to a combination of drug and sun develop a sunburn-like picture. The severity of the reaction is related to the dose of the drug and the duration of sun exposure. The rashes seen in this study varied from erythema (grade 1) to actual blisters (grade 3). The fact that some reaction was noted at the lowest dose level means that COL-3 is a potent photosensitizer. Thus, it is not surprising that at the highest dose levels of drug, the use of titanium dioxide sunblock, which protects in the UVB and UVA ranges, was not sufficient to prevent severe phototoxicity. However, sunblock use did decrease the rate of phototoxicity from 69% to 54% overall. As a class of drugs, the tetracyclines are well-known photosensitizers. Until now, the most potent has been doxycycline, with an incidence of 42%.23 The fact that patients developed the reaction through window glass means that the eliciting wavelength was in the UVA range, ie, more than 3,200 A, because shorter wavelengths are absorbed by glass. This is consistent with the known UV maximums of COL-3, which are 264 and 350 nm.18 The exact reason for COL-3–induced photosensitivity is unknown. Wiebe et al24 elucidated the mechanism of photosensitivity by tetracycline derivatives as a photo-oxidation process. Hasan et al25 reported that the photosensitization of tetracyclines involves an oxygen-dependent pathway that involves a tetracycline photoproduct and possibly singlet oxygen. Follow-up studies show that the phenolic ring, tertiary amino groups, and conjugated double bonds in the tetracycline structure may all be potential reactive sites for the singlet molecular oxygen-mediated photo-oxidation.26 COL-3 contains only the phenolic ring of the tetracycline structure and lacks the other reactive sites noted above. SLE was an unexpected side effect observed in the study. The pathogenesis of the drug-induced lupus noted with COL-3 is also unknown. The only other tetracycline known to cause a similar autoimmune process is minocycline, in which case lupus does not occur until a year or two after initiation of therapy. Shapiro et al27 hypothesized that the dimethylamino group at the C7 position of minocycline or a metabolite derived from this functional group may be responsible for this side effect. For COL-3, SLE occurred within weeks of the start of therapy. COL-3 does not have the C7 dimethylamino group, nor does it have the C4 dimethylamino group that is possessed by the majority of the tetracycline derivatives. Although COL-3 may have been involved in the anemia of six patients, only three patients were studied in detail. At the time of their anemia, those three patients underwent bone marrow examinations that revealed ringed sideroblasts. These abnormal erythroid precursors are distinguished by perinuclear granules of iron that represent iron in mitochondria. They have been observed as a toxic change related to the antituberculin drugs chloramphenicol and ethanol. They have also been observed in myelodysplasia and rare inherited anemias.28-31 In the cases reported here, the ringed sideroblasts presumably reflect COL-3 toxicity to the heme metabolic pathway. In one case, clinical follow-up demonstrated that this process is fully reversible. Large interpatient variability in the derived pharmacokinetic parameters exists and needs to be further explored. As noted above, the absorption of COL-3 seems saturable because the increase in Cmax is not dose-proportional. This saturation may be a result of the insolubility of COL-3 in water (0.01 mg/mL) (S. Esmail Tabibi, personal communication, January 1998), saturation of metabolism by the gut wall, or saturation of first pass metabolism. COL-3 has a long half-life that is 2.1 to 11.0 times longer than any previously studied analog, including doxycycline, demeclocycline, lymecycline, methacycline, minocycline, oxytetracycline, and tetracycline.32-41 This increase in half-life may reflect the lipophilicity of COL-3. The plasma protein binding and drug metabolism are being studied at this time.
Supported by the United States Government, the intramural program of the National Cancer Institute, and the Office of Research on Minority Health, National Institutes of Health. We thank McDonald Horne, MD, for his assistance with the hematologic toxicities, Julian Reed and Raul Alfaro for their technical assistance, and Delmar Henry for data management support.
1. Liotta LA, Stetler-Stevenson WG: Metalloproteinases and cancer invasion. Semin Cancer Biol 1: 99-106, 1990[Medline]
2.
Chambers AF, Matrisian LM: Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89: 1260-1270, 1997 3. Golub LM, Lee HM, Lehrer G, et al: Minocycline reduces gingival collagenolytic activity during diabetes: Preliminary observations and a proposed new mechanism of action. J Periodontal Res 18: 516-526, 1983[Medline] 4. Golub LM, Ramamurthy N, McNamara TF, et al: Tetracyclines inhibit tissue collagenase activity: A new mechanism in the treatment of periodontal disease. J Periodontal Res 19: 651-655, 1984[Medline] 5. Golub LM, Goodson JM, Lee HM, et al: Tetracyclines inhibit tissue collagenases: Effects of ingested low-dose and local delivery systems. J Periodontol 56: 93-97, 1985[Medline] 6. Golub LM, Wolff M, Lee HM, et al: Further evidence that tetracyclines inhibit collagenase activity in human crevicular fluid and from other mammalian sources. J Periodontal Res 20: 12-23, 1985[Medline]
7.
Golub LM, Ramamurthy NS, McNamara TF, et al: Tetracyclines inhibit connective tissue breakdown: New therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med 2: 297-321, 1991
8.
Hanemaaijer R, Visser H, Koolwijk P, et al: Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells. Adv Dent Res 12: 114-118, 1998 9. Ramamurthy NS, Vernillo AT, Greenwald RA, et al: Reactive oxygen species activate and tetracyclines inhibit rat osteoblast collagenase. J Bone Miner Res 8: 1247-1253, 1993[Medline] 10. Smith GNJ, Brandt KD, Hasty KA: Procollagenase is reduced to inactive fragments upon activation in the presence of doxycycline. Ann N Y Acad Sci 732: 436-438, 1994[Medline] 11. Smith GNJ, Brandt KD, Hasty KA: Activation of recombinant human neutrophil procollagenase in the presence of doxycycline results in fragmentation of the enzyme and loss of enzyme activity. Arthritis Rheum 39: 235-244, 1996[Medline] 12. Seftor REB, Seftor EA, De Larco JE, et al: Chemically modified tetracyclines inhibit human melanoma cell invasion and metastasis. Clin Exp Metastasis 16: 217-225, 1998[Medline]
13.
Myers SA, Wolowacz RG: Tetracycline-based MMP: Inhibitors can prevent fibroblast-mediated collagen gel contraction in vitro. Adv Dent Res 12: 86-93, 1998
14.
Lokeshwar BL, Houston-Clark HL, Selzer MG, et al: Potential application of a chemically modified non-antimicrobial tetracycline (CMT-3) against metastatic prostate cancer. Adv Dent Res 12: 97-102, 1998 15. Pruzanski W, Stefanski E, Vadas P, et al: Chemically modified non-antimicrobial tetracyclines inhibit activity of phospholipases A2. J Rheumatol 25: 1807-1812, 1998[Medline] 16. Trachtman H, Futterweit S, Greenwald R, et al: Chemically modified tetracyclines inhibit inducible nitric oxide synthase expression and nitric oxide production in cultured rat mesangial cells. Biochem Biophys Res Commun 229: 243-248, 1996[Medline]
17.
Bettany JT, Wolowacz RG: Tetracycline derivatives induce apoptosis selectively in cultured monocytes and macrophages but not in mesenchymal cells. Adv Dent Res 12: 136-143, 1998 18. Rudek MA, March CL, Bauer KS, et al: High-performance liquid chromatography with mass spectrometry detection for quantitating COL-3, a chemically modified tetracycline, in human plasma. J Pharm Biomed Anal 22: 1003-1014, 2000[Medline] 19. Gibaldi M, Perrier D: Noncompartmental analysis based on statistical moment theory, in Pharmacokinetics, ed 2. New York, NY, Marcel Dekker, 1982, pp 409-417
20.
Simon R, Freidlin B, Rubinstein L, et al: Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89: 1138-1147, 1997 21. Ghate JV, Turner ML, Rudek MA, et al: Drug-induced lupus erythematous associated with COL-3. Arch Dermatol (in press)
22.
Folkman J: Seminars in medicine of the Beth Israel Hospital. Boston: Clinical applications of research on angiogenesis. N Engl J Med 333: 1757-1763, 1995 23. Layton AM, Cunliffe WJ: Phototoxic eruptions due to doxycycline: A dose-related phenomenon. Clin Exp Dermatol 18: 425-427, 1993[Medline] 24. Wiebe JA, Moore DE: Oxidation photosensitized by tetracyclines. J Pharm Sci 66: 186-189, 1977[Medline] 25. Hasan T, Kochevar IE, McAuliffe DJ, et al: Mechanism of tetracycline phototoxicity. J Invest Dermatol 83: 179-183, 1984[Medline] 26. Miskoski S, Sanchez E, Garavano M, et al: Singlet molecular oxygen-mediated photo-oxidation of tetracyclines: Kinetics, mechanism and microbiological implications. J Photochem Photobiol B 43: 164-171, 1998[Medline] 27. Shapiro LE, Knowles SR, Shear NH: Comparative safety of tetracycline, minocycline, and doxycycline. Arch Dermatol 133: 1224-1230, 1997[Abstract] 28. MacGibbon BH, Mollin DL: Sideroblastic anemia in man: Observations on seventy cases. Br J Haematol 11: 59-69, 1965[Medline] 29. Saidi P, Wallerstein RO, Aggeler PM: Effect of chloramphenicol on erythropoiesis. J Lab Clin Med 57: 247-256, 1961[Medline] 30. Verwilghen R, Reybrouck G, Callens L, et al: Antituberculous drugs and sideroblastic anemia. Br J Haematol 11: 92-95, 1965[Medline] 31. Bowman WD: Abnormal ("ringed") sideroblasts in various hematologic and non-hematologic disorders. Blood 18: 662-671, 1962 32. Campistron G, Coulais Y, Caillard C, et al: Pharmacokinetics and bioavailability of doxycycline in humans. Arzneimittelforschung 36: 1705-1707, 1986[Medline]
33.
Welling PG, Koch PA, Lau CC, et al: Bioavailability of tetracycline and doxycycline in fasted and nonfasted subjects. Antimicrob Agents Chemother 11: 462-469, 1977 34. Wojcicki J, Kalinowski W, Gawronska-Szklarz B: Comparative pharmacokinetics of doxycycline and oxytetracycline in patients with hyperlipidemia. Arzneimittelforschung 35: 991-993, 1985[Medline] 35. Kunin CM, Finland M: Demethylchlortetracycline: A new tetracycline antibiotic that yields greater and more sensitive antibacterial activity. N Engl J Med 259: 999-1005, 1958 36. Johnston A, Hedges A, Turner P: A study of the interaction between oxytetracycline and pyridostigmine. Hum Toxicol 7: 263-266, 1988[Medline] 37. Seitz C, Garcia P, Arancibia A: Influence of ethanol ingestion on tetracycline kinetics. Int J Clin Pharmacol Ther 33: 462-464, 1995[Medline] 38. Schreiner A, Digranes A: Pharmacokinetics of lymecycline and doxycycline in serum and suction blister fluid. Chemotherapy 31: 261-265, 1985[Medline] 39. Bernard B, Yin EJ, Simon HJ: Clinical pharmacologic studies with minocycline. J Clin Pharmacol New Drugs 11: 332-348, 1971[Abstract] 40. Doluisio JT, Dittert LW: Influence of repetitive dosing of tetracyclines on biologic half-life in serum. Clin Pharmacol Ther 10: 690-701, 1969[Medline] 41. Kunin CM: Comparative serum binding, distribution and excretion of tetracycline and a new analogue, methacycline. Proc Soc Exp Biol Med 110: 311-315, 1962 Submitted April 21, 2000; accepted September 7, 2000. This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
) was calculated with the linear trapezoidal method. The terminal half-life (T1/2) was determined from the terminal slope on a log-linear plot of concentration versus time. Total apparent clearance (ClT/F) was calculated as dose divided by AUC0-
