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PubMed1998

Liquid-liquid extraction procedure for trace determination of cyclophosphamide in human urine by high-performance liquid chromatography tandem mass spectrometry.

A sensitive, specific and accurate high performance liquid chromatography/ionspray-tandem mass spectrometry procedure (HPLC/MS/MS) has been developed to quantify cyclophosphamide in human urine from hospital personnel involved in drug preparation and administration of antineoplastic alkylating agents. This methodology, which includes liquid-liquid extraction with ethylacetate, requires no derivatization procedures, preventing cyclophosphamide (CP) from possible thermal and chemical decomposition reactions. We detected the excretion of this unmetabolized alkylating drug in 50% of all the study participants. The amount of CP ranged from 0.1 ng microL-1 to 1.9 ng microL-1 urine. This methodology was validated by the use of ifosfamide as internal standard. The assay was linear over the range 0 to 3.2 ng microL-1 urine, with a lower limit of quantification of 0.2 microL-1. The limit of detection was assessed at 0.05 ng microL-1 urine. This method is characterized by a coefficient of variation < 10%. Standard calibration curves, obtained on three different days, had correlation coefficients always greater than 0.998. The intra and interday precision were within 11%, and accuracy was in the range 99-103%. The mean extracted recovery assessed at three different concentrations (0.5, 0.8, 3.2 ng microL-1) was always more than 85%. The extraction efficiency of cyclophosphamide from urine samples was also studied at six different pH values (pH 4, 5, 6, 7, 8, 10). The maximum extraction efficiency was obtained when the pH of urine solutions was adjusted to 7.0

Antineoplastic Agents, Alkylating↗
PubMed1975

Effects of cyclophosphamide and adriamycin on the healing of surgical wounds in mice.

Administration of therapeutic dose levels of cyclophosphamide as a single dose or as daily treatments for 5 days during the perisurgical period resulted in a significant decrease in the strength of surgical skin wounds in mice as measured 21 days after surgery. Administration of a single dose of 200 mg/kg either at the time of surgery or up to 4 days prior to or after surgery impaired 21-day wound strength, with the most extensive depression observed when the drug was given 1 or 2 days after surgery. Earlier stages of wound healing (day 3 or day 7) were not as sensitive to cyclophosphamide. Adriamycin in the therapeutic dosage range for mice did not significantly impair wound healing. This drug had an effect only at the LD10 dosage level. Combination treatment with cyclophosphamide plus adriamycin at the time of surgery impaired 21-day wound strength to a greater degree than observed with either agent alone, but did not significantly depress wound strength 3 or 7 days after surgery. These studies indicate that dosage level, the time of drug administration relative to surgery, and the time at which wound strength measurements are made are important parameters in determination of the effects of antineoplastic agents on wound healing.

Animals↗
PubMed1976

Urinary-bladder toxicity following pelvic irradiation and simultaneous cyclophosphamide therapy.

The frequency and severity of urinary-bladder toxicity were determined retrospectively in a large series of childhood cancer patients treated with either pelvic irradiation and simultaneous cyclophosphamide or cylclophosphamide with extrapelvic irradiation. Of 50 patients who received the first combination, 17 (34%) developed urinary-bladder toxicity. Eight of the 17 had transient hematuria and dysuria with complete clearing clinically after cessation of treatment; nine had chronic or intermittent hematuria which persisted after treatment was stopped and often resulted in demonstrable fibrosis and telangiectasia of the bladder. By contrast, of 60 children who received cyclophosphamide and radiotherapy outside the pelvic region, only five (8%) developed hematuria and in all instances it was transient. This comparative study demonstrates a significantly increased frequency and severity of urinary-bladder toxicity in cancer patients receiving pelvic irradiation with simultaneous cyclophosphamide.

Adolescent↗
PubMed1979

Combination chemotherapy for advanced breast cancer utilizing vincristine, adriamycin, and cyclophosphamide (VAC).

Thirty-two patients with advanced breast cancer were treated with a combination of vincristine (1 mg/m2, not exceeding 2 mg, administered intravenously on day 1), adriamycin (40 mg/m2 administered intravenously on day 1), and cyclophosphamide (200 mg/m2 administered orally for 4 days on days 3-6). Courses were repeated at 21-28-day intervals. The mean age of the patients was 57 years (range, 30-79 years) and 18 patients were postmenopausal. None of the patients had received prior chemotherapy although 15 had prior endocrine treatment. Objective response was observed in 23 (72%) of the 32 patients and 9 responses (28%) were complete. The median remission duration was estimated to be 22 months. Median survival has not been reached but exceeds 24 months with a median time of follow-up of 17 months. Toxicity was acceptable and included mild nausea, vomiting, alopecia, and paresthesias. Only one instance of serious infection and no instances of bleeding were observed. The addition of vincristine to combination chemotherapy with adriamycin and cyclophosphamide appears to prolong the remission duration and survival in patients with advanced breast cancer to a greater extent than is achieved with adriamycin and cyclophosphamide alone.

Adult↗
PubMed1979

VP 16-213 (VP 16) and cyclophosphamide in the treatment of primitive lung cancer in phase M 1.

Sixty patients suffering from primitive lung cancer in Phase M 1 were included in two successive chemotherapy Protocols, 30 patients to a group. The first of these (an attempt at cellular synchronization by combining VCR-Cyclophosphamide-Prednisone) is used as a historical group as compared to the second. In the second protocol the combination of VP 16.213 (100 mg/m2, po, day X 5 days) and cyclophosphamide (100 mg/m2, ev, day X 5 days) was attempted. The positive results obtained (more than 60% of the responses were above 50%) together with low toxicity was not accompanied by improvement of survival with respect to that observed in international medical literature. On the other hand, the number of cases studied--30 patients--was too low to permit a better evaluation of our results. Despite this fact, it seems appropriate to continue clinical investigation of the VP 16.213-Cyclophosphamide combination in lung cancer.

Adult↗
PubMed1979

Ftorafur, adriamycin, cyclophosphamide and BCG in the treatment of metastatic breast cancer.

Ftorafur is a 5-fluorouracil analogue which is slowly metabolized to 5-FU, resulting in prolonged therapeutic levels of this latter drug. Ninety-one evaluable patients with metastatic breast cancer were treated with Ftorafur, Adriamycin, cyclophosphamide, and BCG (ACFTOR-BCG), in an attempt to increase the effectiveness of the program or decrease its myelosuppressive toxicity. The results of this trial were compared to those previously reported with the combination of 5-FU, Adriamycin, cyclophosphamide, and BCG (FAC-BCG). Overall objective response rates were 65% and 76% for ACFTOR-BCG and FAC-BCG, respectively. Durations of response were 12 months and 14 months for ACFTOR-BCG and FAC-BCG (p = 0.53). The median survival of responders was 22 and 23.9 months, respectively. Substantial toxicity was observed with Ftorafur: nausea and vomiting severe enough to cause weight loss was observed in a substantially higher fraction of the patients treated with this drug than with 5-FU. Other side-effects, which were not observed with the 5-FU combination, were somnolence, dizziness, personality changes, tremor, ataxia, and confusion. No differences in myelosuppressive toxicity were observed between the two combinations, and the incidence of infectious complications was identical. The combination of Ftorafur, Adriamycin, cyclophosphamide and BCG did not offer any advantages with respect to increased effectiveness or reduced toxicity over the FAC-BCG regimen in breast carcinoma.

Adult↗
PubMed1980

Combination chemotherapy with adriamycin-cyclophosphamide for advanced ovarian carcinoma.

Combination chemotherapy with Adriamycin-cyclophosphamide was employed after surgical treatment in 60 women with Stage III-IV ovarian adenocarcinoma. Of 53 evaluable patients, objective response was noted in 34 of 41 (83%) without prior cytotoxic therapy but in only two of 12 (17%) who had failed a single alkylating agent or radiotherapy (P < .005). Complete response was confirmed by a negative biopsy at the site(s) of prior disease in 12 patients. Eleven of the 12 biopsy-confirmed complete responses were achieved in patients without pretreatment palpable tumor. Twenty-four out of 41 patients with palpable masses responded but only one was confirmed as complete. Confirmed complete responses had a median duration of 24 months, whereas the median duration of all other responses was only seven months. The median survival for patients in whom Adriamycin-cyclophosphamide was the initial chemotherapy was 24 months. The median survival in patients with palpable tumor exceeds that of historical controls matched for age, tumor cell type, and grade (P = .05); the median survival for the confirmed complete responders has not been reached. The toxicity of this regimen was acceptable at doses of Adriamycin and cyclophosphamide of 45 mg and 500 mg/M2 body surface area, respectively. Extensive excision of tumor followed by effective combination chemotherapy offers the best current approach toward improved patient survival in advanced ovarian cancer.

Adenocarcinoma↗
PubMed1984

Pharmacokinetics of "activated" cyclophosphamide and therapeutic efficacies.

Estimation of "activated" cyclophosphamide (4-OH-CP) in blood of cancer patients and laboratory animals has revealed significant differences between pharmacokinetics of cyclophosphamide (CP) in man and laboratory animals after CP treatment. Whereas in blood of mice and rats relatively high concentrations of 4-OH-CP were found to exist for a relatively short time, in blood of humans only low, but longer-lasting, blood levels were detected after administration of comparable CP doses. In order to examine whether these different pharmacokinetic behaviors might account at least in part for the known differences of antitumor activity and toxicity of CP between humans and laboratory animals, the authors studied the influence of pharmacokinetics of activated CP on therapeutic efficacy and toxicity after injection of 4-(S-ethanol)-sulfido-cyclophosphamide (P1), a pro drug of activated CP, into nude mice bearing heterotransplanted human bladder sarcoma. With P1, which hydrolyzes quickly in blood to yield 4-OH-CP, different blood level shapes of 4-OH-CP could be established either by single bolus injection of P1 or by repetitive injection of a loading dose followed by several maintenance doses which caused nearly constant levels of activated CP for a longer time period. With these models it was found that 4-OH-CP showed more therapeutic efficacy when present in blood at relatively low levels for longer times than after bolus injection of the same dose resulting in a sharp peak level of activated CP. So after single intraperitoneal (IP) injection of 300 mg/kg P1 which caused a bioavailability of 36 mumol/ml-1/minute a 67% inhibition of tumor growth was achieved, whereas a tumor growth reduction of 83% was obtained after injection of the same dose in 6 fractions resulting in constant blood levels with a bioavailability of only 17 mumol/ml-1/minute. In contrast to the significant influence on antitumor efficacy of activated CP, practically no effect of pharmacokinetics on toxicity of 4-OH-CP could be observed. Therefore, the bioavailability of activated CP, which killed 50% of the animals, was determined to be approximately 89 mumol/ml-1/minute after adjustment of pharmacokinetics to yield constant levels and approximately 79 mumol/ml-1/minute after single bolus injection. The experiments presented show that by adjustment of pharmacokinetics the therapeutic index of P1, defined as bioavailability causing 50% of animals to die, referred to bioavailability causing 90% tumor growth inhibition, could be more than doubled.

Animals↗
PubMed1984

Treatment of advanced and recurrent ovarian carcinoma with cyclophosphamide, doxorubicin, and cisplatin.

Forty-seven patients with primary advanced (N = 37) or recurrent ovarian carcinoma (N = 10) completed a 12-month course of CAP chemotherapy or developed progressive disease while on therapy and were evaluated. All patients were treated between August 1, 1977 and August 1, 1982. Cyclophosphamide 400 mg/m2, Adriamycin (doxorubicin) 40 mg/m2, and cisplatin 60 mg/m2, were administered every 4 weeks intravenously. After 8 courses the cisplatin was stopped. The patients then received 500 mg/m2 of cyclophosphamide and 50 mg/m2 of Adriamycin. At the cumulative dose of 450 mg/m2, the Adriamycin was stopped and cyclophosphamide was given at 1 g/m2 alone until the patient had received a total of 12-13 courses from the initiation of the chemotherapy protocol. The cardiac, renal, and hematopoetic toxicity of the regimen was mild to moderate. The median survival of the entire study population was 32 months. The median survival of the patients with primary disease was 36 months. The median survival of patients with recurrent disease was 20 months. There was a significant difference in median survival based on size of the largest lesion prior to initiation of chemotherapy. There was no difference in median survival based on tumor grade or comparing Stage III to Stage IV tumors. The most important aspects of the study appeared to be the length of the median survival of the patients, the fact that all patients who were complete responders and who were considered to have no evidence of disease, have been documented by second look, and the success of secondary treatment after second-look procedures revealed persistent tumor. The authors additionally report the use of weight change as an indicator of tumor response, and the importance of the pelvic examination complimented by fine-needle aspiration in following the course of these patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Radiation-induced lung fibrosis after treatment of small cell carcinoma of the lung with very high-dose cyclophosphamide.

Twenty-five previously untreated patients with small cell carcinoma of the lung were treated with cyclophosphamide 160 to 200 mg/kg (with autologous bone marrow support) followed by radiotherapy (4000 cGy) to the primary site and mediastinum. No other treatment was given until relapse occurred. Nineteen patients were assessable at least 4 months after radiotherapy; of these, 15 (79%) developed radiologic evidence of fibrosis, which was symptomatic in 14 (74%). The time of onset of fibrosis was related to the volume of lung irradiated. A retrospective analysis was made of 20 consecutive patients treated with multiple-drug chemotherapy and an identical radiotherapy regimen as part of a randomized trial. Radiologic and symptomatic fibrosis was one half as frequent (35%) as in the high-dose cyclophosphamide group. Very high-dose cyclophosphamide appears to sensitize the lung to radiotherapy and promotes the production of fibrosis.

Adult↗
PubMed1985

Leimyosarcoma of the urinary bladder. 13 years after cyclophosphamide therapy for Hodgkin's disease.

A leiomyosarcoma of the urinary bladder occurred in a 17-year-old boy who was treated with a total dose of 67 g cyclophosphamide over a period of 5 years for Hodgkin's disease diagnosed at the age of 4. Cyclophosphamide was discontinued at the age of 9 because of gross hematuria, and intermittent hematuria recurred 8 years after (at the age of 17) the cessation of this drug. A large exophytic tumor found in the urinary bladder was diagnosed as leiomyosarcoma by light and electron microscopic studies. In addition, there were microscopic features of long-term cyclophosphamide toxicity throughout the bladder wall.

Adult↗
PubMed1986

A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. A Gynecologic Oncology Group Study.

A randomized clinical trial was conducted in women with bulky (suboptimal) Stage III and Stage IV ovarian carcinoma, using doxorubicin (Adriamycin) and cyclophosphamide with or without cisplatin. There were 440 evaluable cases, of which 227 had measurable disease. One hundred twenty of these latter patients were treated with cyclophosphamide and doxorubicin (CA), while 107 received cyclophosphamide, doxorubicin and cisplatin (CAP). The clinical complete response (CR) rate for CA was 26% (31/120) compared with 51% (55/107) for CAP (P = less than 0.0001). Of 23 CRs receiving CA who had a second-look laparotomy, only four were negative; of 39 CRs receiving CAP and a second-look, 13 were negative (not statistically significant). The response duration for patients with measurable disease (median 14.6 versus 8.8 months), progression-free interval for all patients (13.1 versus 7.7 months), and survival for patients with measurable disease (19.7 versus 15.7 months) showed a statistically significant advantage for CAP; however, there was no difference in survival of patients with nonmeasurable disease. Toxicity was more severe with CAP but was tolerable. Thus, the addition of cisplatin improves the chemotherapy of advanced ovarian carcinoma.

Adult↗
PubMed1987

High-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone for remission induction in refractory adult acute leukemia.

Fifteen consecutive patients with refractory adult acute leukemia (RAAL) were treated with a combination of high-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone (Hi-COAP). The initial nine patients received cyclophosphamide 350 mg/m2 as a 24-hour intravenous (IV) infusion over 5 days; cytarabine, 100 mg/m2 IV bolus every 12 hours for ten doses; vincristine, 2.0 mg IV bolus on day 1; and prednisone, 100 mg orally for 7 days. The last six patients had the cyclophosphamide infusion lengthened to 7 days, and the cytarabine increased to 14 doses. All patients were evaluable for toxicity and response. Seven patients (47%) obtained a complete remission and six patients (40%) a partial remission. Median duration of all remissions has been 7.0 months with a range of 1 to 32 months. Toxicity has been limited to primarily myelosuppression with no hemorrhagic cystitis, central nervous system (CNS), hepatic, or pulmonary toxicity noted. Gastrointestinal toxicity was mild, with no effect on nutritional status noted. Median duration of complete responders was 8.5 months. Thus, Hi-COAP demonstrates promising efficacy with minimal toxicity in RAAL and warrants further exploration in multiinstitutional trials.

Acute Disease↗
PubMed1992

Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas.

BACKGROUND: Treatment of cancer with multiple-drug chemotherapy regimens or radiation therapy can cause either temporary azoospermia of various durations or permanent azoospermia in young men. METHODS: To identify which drugs in which doses contribute to long-term or permanent azoospermia, semen analyses were done on patients with Ewing and soft tissue sarcomas before, during, and after treatment with either CYADIC (cyclophosphamide, doxorubicin, and dacarbazine), or CYVADIC (vincristine added to CYADIC). Some patients also received other drugs or radiation therapy. RESULTS: From pretreatment levels that were similar to those of control subjects, sperm production declined to azoospermia within 4 months of treatment. Sperm production returned in some patients after treatment; 40% of men recovered to normospermic levels by 5 years after treatment. Few patients showed continued recovery of sperm production after that time. The cumulative dose of cyclophosphamide was the most significant determinant of recovery to normospermic levels; approximately 70% of those who had received doses less than 7.5 g/m2 (median, 4.1 g/m2) recovered, but only 10% recovered when doses exceeded 7.5 g/m2. CONCLUSIONS: Thus, a risk of permanent sterility is associated with the use of the CYADIC and CYVADIC regimens in young men, especially when the cumulative dose of cyclophosphamide is greater than 7.5 mg/m2.

Adult↗
PubMed1993

Feasibility of dose-intensive continuous 5-fluorouracil, doxorubicin, and cyclophosphamide as adjuvant therapy for breast cancer.

BACKGROUND: Several studies support the belief that the efficacy of adjuvant chemotherapy in breast cancer is related to the dose intensity of the chemotherapy used (expressed in milligrams per square meter per week). Retrospective analyses indicate that the actual delivered dose intensity may correlate more strongly with efficacy than the intended dose delivery. METHODS: A doxorubicin-based adjuvant regimen was studied for breast cancer. It was modeled on the Southwest Oncology Group's regimen of cyclophosphamide, methotrexate, and 5-fluorouracil in that daily oral cyclophosphamide and weekly intravenous 5-fluorouracil were used, but weekly doxorubicin was substituted for methotrexate and administered in both the adjuvant and neoadjuvant setting to 29 patients. RESULTS: The actual dose delivery was 1.21-1.24-fold that calculated for the delivered dose in the two other adjuvant regimens using the same three drugs (5-fluorouracil, doxorubicin, and cyclophosphamide) for which this could be determined. This regimen was tolerated well. Toxicity was minimal and consisted largely of expected neutropenia. CONCLUSIONS: Whether improved dose intensity can be increased further with the use of growth factors or actually confers improved outcomes awaits the results of larger future trials.

Adult↗
PubMed1994

High-dose cisplatin, etoposide, and cyclophosphamide with autologous stem cell reinfusion in patients with responsive metastatic or high-risk primary breast cancer.

BACKGROUND: This study was designed to establish the feasibility of combining high-dose cisplatin, etoposide, and cyclophosphamide followed by stem cell rescue in patients with responsive metastatic or high-risk primary breast cancer. METHODS: Eligibility criteria included the presence of high-risk primary breast cancer (Stage II with 10 or more involved axillary nodes or Stage IIIA or B) or Stage IV disease in complete or partial response; physiologic age 50 years or younger; Karnofsky performance status of 80% or greater; and creatinine clearance of 80 ml/minute or greater. Chemotherapy consisted of escalating doses of cisplatin (50-150 mg/m2 intravenously [IV]) given on days -12 and -5, etoposide (30 mg/kg IV) given on days -12 and -5, and cyclophosphamide (100 mg/kg IV) on day -3. On day 0, autologous bone marrow with or without peripheral stem cells, or granulocyte colony-stimulating factor primed peripheral stem cells alone were reinfused. RESULTS: Thirty patients were enrolled in this study. Twenty-eight patients demonstrated no evidence of persistent renal damage after treatment. Two patients suffered symptomatic peripheral neuropathy, and one patient required a hearing aid 3 months after therapy. Hematopoietic toxicities were acceptable. There were two fatalities; Streptococcus viridans bacteremia and adult respiratory distress syndrome developed in one patient; and one patient who received 262 mg/m2 of cisplatin died of renal failure. Twelve of 18 assessable patients with Stage IV disease are without evidence of progression; 3 of these patients are progression-free at 11+, 12+, and 32+ months. With a median follow-up of 16+ months (range, 4-31 months), 7 patients of the group of 11 treated with high-risk primary breast cancer are without evidence of disease. CONCLUSIONS: The Phase II dose of cisplatin when given on a day -12 and day -5 schedule in combination with etoposide and cyclophosphamide has been established at a total of 250 mg/m2. Dose-limiting toxicity has been defined as renal failure, and response rates were comparable to previously reported high-dose chemotherapeutic regimens.

Adenocarcinoma↗
PubMed1994

High-dose doxorubicin, etoposide, and cyclophosphamide with stem cell reinfusion in patients with metastatic or high-risk primary breast cancer. City of Hope Bone Marrow Oncology Team.

BACKGROUND: Chemotherapy with a doxorubicin-containing regimen results in high overall response rates in the treatment of metastatic adenocarcinoma of the breast; the combination of doxorubicin, etoposide, and cyclophosphamide has produced a response rate of 84% in untreated patients with stage IV disease. Recent data suggest that selected groups of patients with metastatic disease treated with high-dose chemotherapy and stem cell support may enjoy unmaintained, long-term remission. This study was designed to establish the feasibility of administering the combination of high-dose infusional doxorubicin, etoposide, and cyclophosphamide followed by autologous stem cell rescue in patients with responsive metastatic, or high-risk primary breast cancer. METHODS: Criteria for patient enrollment included the presence of high-risk primary breast cancer (stage II with > or = 10 involved axillary nodes or stages III A or B) or stage IV disease in complete or partial response; Karnofsky performance status of 80% or more; no prior radiation therapy to the left side of the chest; exposure to a 150-mg/m2 or smaller cumulative dose of doxorubicin, and a ventricular ejection fraction of 55% or more. Chemotherapy consisted of escalating doses of doxorubicin given by a 96-hour continuous intravenous infusion, followed by 60 mg/kg of etoposide and 100 mg/kg cyclophosphamide, both given intravenously. On Day 0, autologous bone marrow with or without peripheral stem cells, or granulocyte colony-stimulating factor primed peripheral stem cells alone were reinfused. RESULTS: Thirty-five patients were treated in this study. There were no treatment-related deaths. No patient had a decrease in cardiac ejection fraction below 50% as a consequence of high-dose chemotherapy. Two patients suffered grade 3 mucositis at the highest level of doxorubicin (200 mg/m2). Of 21 patients treated for primary high-risk breast cancer, 19 are recurrence free, with a median follow-up of more than 8 months (> or = 4-36 months). Five of fourteen patients with stage IV disease remain progression free at greater than or equal to 5, 7, 9, 15, and 42 months. For patients with stage IV breast cancer, the median progression-free survival after high-dose chemotherapy was 9 months; the median overall survival had been reached at 22 months. CONCLUSIONS: The phase II dose of doxorubicin in this combination therapy has been established at 165 mg/m2, with dose-limiting toxicity defined as mucositis. Further trials to define the role of this safe and effective high-intensity regimen in the treatment of breast cancer are indicated.

Adenocarcinoma↗
PubMed2000

Paternal exposure to cyclophosphamide dysregulates the gene activation program in rat preimplantation embryos.

Although there has been progress in determining the mechanisms by which maternal toxicant exposure affects progeny, there is little information on the actions of drugs administered to the father. We investigated the effects of pre-conceptional paternal exposure to cyclophosphamide, an anti-cancer agent, on embryonic gene activation in the rat. The male pronucleus was formed earlier in embryos sired by cyclophosphamide-treated male rats than in those sired by controls; early male pronucleus formation was followed by alterations in the gene activation program. BrUTP incorporation into RNA and Sp1 transcription factor immunostaining were increased and spread over both cytoplasmic and nuclear compartments in 2-cell embryos sired by cyclophosphamide-treated males compared to controls. Total RNA synthesis was constant in 1-8 cell embryos sired by drug-treated fathers, while in control embryos RNA synthesis increased four-fold to peak at the 4-cell stage. In 2-cell embryos sired by drug-treated males, the relative abundance of candidate imprinted genes was elevated significantly above control; a peak in the expression of these genes was not observed until the 8-cell stage in control embryos. Thus, paternal drug exposure temporally and spatially dysregulated rat zygotic gene activation, altering the developmental clock.

Animals↗