Table 1. Impact Timed Weekly TPZ Administration During Metronomic CPA Treatment on 9L Tumors (~350mm³).

Rat 9L gliosarcoma tumors were grown in male ICR scid mice. When tumor size reached ~350 mm³ (Table 1) or ~1200 mm³ (Table 2), drugs CPA was injected at a single dose of 140mg/Kg BW i.p. every 7 days, while TPZ was injected at 5mg/Kg every 7 days alone or in combination with CPA (140mg/Kg. i.p.) at days 1, 2, and 3 (Table 1) or at days 3, 4, 5 and 6 (Table 2) after each CPA injection. Tumor sizes were monitored twice a week along with BWs. A total of 9 CPA and 9 TPZ injections were used to treat all CPA and TPZ groups thus receiving the same cumulative doses of the drugs. Untreated and animals treated with CPA/TPZ at day 6 were killed due to large tumor sizes. Statistical comparison of treatment impacts at the initial phase of treatment (period between 2^nd and 4^th CPA/TPZ injections) between day 1 and 2 compared to day 3 (*: p<0.05), and at the end of treatment between days 1 and 2 compared to day 3 (*: p<0.05 and **: p<0.01 respectively) using One way anova Bonferroni’s Multiple Comparison test were performed using Prism software version 4 (GraphPad Software, San Diego, CA)

	Initial Response to CPA
	Initial Tumor Vola	Continued Tumor Growth Periodb	Tumor Size Increasec	Maximal Tumor Regressiond	Tumor-free Periode	Tumors Eradicatedf	Body Weight Lossg
	mm3	days	%	%	days	number	%
9L	352 ± 55	15 (killed)	2071 ± 437	0	0	0/8	N/A
9L + CPA/7 d	346 ± 102	11–19 (16.7 ± 3.2)	671 ± 213	100(3/8)	27	1/8	7.4%
9L + TPZ/7 d	375 ± 80	15 (killed)	2349 ± 514	0	0	0/8	N/A
9L + CPA7/TPZd1	342 ± 72	8–15 (12.7 ± 3.2)	678 ± 142	100(5/8)	25 ± 7.15	1/8	2.4%
9L + CPA7/TPZ d2	379 ± 55	11–19 (16 ± 3.5)	612 ± 96	100 (4/8)	33 ± 11.5	1/8	4.6%
9L + CPA7/TPZ d3	336 ± 66	8–19 (14.1 ± 4.4)	463 ± 72	100(8/8)	53 ± 2**/*	4/8	1%

^bTime, measured in days after first CPA injection, until tumor regression was first detected in tumor size measurements taken twice/week. Data are expressed as a range exhibited by the individual tumors in each group. Untreated 9L tumor controls, 9L TPZ treated tumors (Table 1) and 9L + CPA7/TPZ d6 (Table 2) did not regress; mice were killed 15 d or 21 d after initiation of CPA treatment in the other groups.

^cPercentage increase in tumor size from time of first CPA injection until mice were killed (untreated 9L controls) or tumor regression was first observed (treated tumors), mean ± SE.

^dMaximal decrease in tumor size, which generally was achieved after 6–9 CPA/TPZ injections. Percentage regression values were calculated based on the vol of each tumor at the time of first CPA injection (c.f., column 1) (mean ± SE).

^eLength of tumor-free periods before growth resumed after cessation of CPA/TPZ treatment. Data are expressed as mean ± SE days.

^fNumber of tumors that were not palpable during the experiment and did not regrow.

^gBody weight loss was calculated as the change from untreated body weight of animals at the start of treatment.

^aTumor vol at time of first CPA injection, mean ± SE for (n=8, 4 animals/group) individual tumors, calculated from measured tumor areas.